Anti-CML activity of alkaloids.
\r\n\tA quark exhibits confinement, which means that the quarks are not observed independently but always in combination with other quarks. This makes determining the properties (mass, spin, and parity) impossible to measure directly; these traits must be inferred from the particles composed of them. There are six flavors of quarks: up, down, strange, charm, bottom, and top. The flavor of the quark determines its properties.
\r\n\tThere are three generations of quarks, based on pairs of weak positive/negative, weak isospin. The first generation quarks are up and down quarks, the second-generation quarks are strange and charm quarks, the third generation quarks are top and bottom quarks. The up and down quarks make up protons and neutrons, seen in the nucleus of ordinary matter. They are the lightest and most stable. The heavier quarks are produced in high-energy collisions and rapidly decay into up and down quarks.
\r\n\tThe baryons and mesons known at the time fell into symmetric families of multiplets (octuplets, decuplets) sharing two identical quantum numbers (spin and parity), but differing in an ordered way in others (mass, charge, baryon number and strangeness). The mathematical group to fit this complex situation-SU3, the symmetric, unitary group of dimension 3-was proposed independently by Gell-Mann and Ne'eman. The validity of SU3 was demonstrated by the experiment. A major prediction was that a particle (the omega-minus), an isotopic singlet with spin = 3/2, positive parity, mass of roughly 1,680 MeV, negative charge, baryon number +1, strangeness = -3, and stable to strong decay, should exist to complete the 3/2+ baryon decuplet. It was therefore a major triumph for the scheme when the omega-minus, a baryon with the precise mass, charge, and strangeness predicted, was discovered in 1964. All these facts introduced a quark idea fully into modern physics.
\r\n\r\n\tThis book will be a self-contained collection of scholarly papers targeting an audience of practicing researchers, academics, PhD students and other scientists. The contents of the book will be written by multiple authors and edited by experts in the field.
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Habilitation: „Triggers in the Pierre Auger Observatory: Designs, Implementation and the Impact on the Experimental Results”.\r\nDevelopment of the FPGA-based 2nd level trigger for 24 fluorescence detectors and 1st level trigger for 1660 surface detectors of the Pierre Auger Observatory, FPGA based filters suppressing radio-frequency interferences (RFI) in radio detector of Auger Engineering Radio Array, FPGA based triggers for the Auger surface detectors dedicated for a recognition of very inclined EAS induced by 'old” proton showers or 'young” neutrino showers.\r\nDr. Szadkowski has worked as a research scientist in Michigan Technological University, Associate Professor in College de France, Senior Wissenschaftler, Bergische Universität Wuppertal, and currently is working as the head of the Department of High-Energy Astrophysics and as an Associate Professor at the University of Łódź.",institutionString:"University of Łódź",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"4",totalChapterViews:"0",totalEditedBooks:"1",institution:{name:"University of Łódź",institutionURL:null,country:{name:"Poland"}}}],coeditorOne:null,coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"20",title:"Physics",slug:"physics"}],chapters:[{id:"73971",title:"The Inter-Nucleon Up-to-Down Quark Bond and its Implications for Nuclear Binding",slug:"the-inter-nucleon-up-to-down-quark-bond-and-its-implications-for-nuclear-binding",totalDownloads:56,totalCrossrefCites:0,authors:[null]}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"247041",firstName:"Dolores",lastName:"Kuzelj",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/247041/images/7108_n.jpg",email:"dolores@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. 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Venkateswarlu",coverURL:"https://cdn.intechopen.com/books/images_new/371.jpg",editedByType:"Edited by",editors:[{id:"58592",title:"Dr.",name:"Arun",surname:"Shanker",slug:"arun-shanker",fullName:"Arun Shanker"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}},{type:"book",id:"878",title:"Phytochemicals",subtitle:"A Global Perspective of Their Role in Nutrition and Health",isOpenForSubmission:!1,hash:"ec77671f63975ef2d16192897deb6835",slug:"phytochemicals-a-global-perspective-of-their-role-in-nutrition-and-health",bookSignature:"Venketeshwer Rao",coverURL:"https://cdn.intechopen.com/books/images_new/878.jpg",editedByType:"Edited by",editors:[{id:"82663",title:"Dr.",name:"Venketeshwer",surname:"Rao",slug:"venketeshwer-rao",fullName:"Venketeshwer Rao"}],productType:{id:"1",chapterContentType:"chapter",authoredCaption:"Edited by"}}]},chapter:{item:{type:"chapter",id:"53278",title:"Natural Products for Treatment of Chronic Myeloid Leukemia",doi:"10.5772/66175",slug:"natural-products-for-treatment-of-chronic-myeloid-leukemia",body:'Chronic myeloid leukemia (CML) is a hematoproliferative neoplasm that is marked by uncontrolled myeloid cell divisions in the bone marrow [1]. CML arises due to a reciprocal translocation between chromosome 9 and chromosome 22 [(9;22) (q34;q11)], eventually culminating in the genesis of the bcr-abl oncogene. Approximately 90% of CML patients have shortened chromosome called “Philadelphia chromosome” (Ph) [2].
The bcr-abl oncogene encodes a constitutively activated tyrosine kinase, BCR-ABL. The catalytically activated kinase, in turn, activates multiple cell proliferatory signaling pathways such as RAS, a small GTPase, mitogen activated protein kinase (MAPK), signal transducers and activator of transcription (STAT), and phosphoinositide-3-kinase (PI3K) pathways [3].
Targeting Abl kinase is clearly a proven successful strategy to combat CML. First generation tyrosine kinase inhibitor (TKI), imatinib, also known as Gleevac or STI571 inhibited BCR-ABL and suppressed CML progression [4]. Second generation TKIs such as nilotinib, dasatinib & bosutinib and third generation TKIs (Ponatinib) that are more potent to inhibit BCR-ABL kinase are currently used to treat CML [5, 6]. All these TKIs were approved by the US Food and Drug Administration (FDA). TKIs have changed the clinical course of CML. However, mutations in bcr-abl and multi-drug resistance (MDR) due to efflux of the drug as a result of overexpression of p-glycoprotein (p-gp) make TKIs less effective. Primary or secondary resistance to TKIs therapy still exists; however, there is a constant need for alternative therapeutic strategy (Figure 1) [7].
Schematic representation of NPs and TKIs on BCR-ABL inhibition and downregulation of downstream signaling pathways (NP—natural products, TKI—tyrosine kinase inhibitor, CML—chronic myeloid leukemia, MDR—multi-drug resistance).
Natural products (NPs) represent a large family of diverse secondary metabolites with profound biological activities. NPs are produced in several organisms like bacteria, fungi, plants and marine animals. NPs are inexpensive and have less (or) no side effects; hence, NPs are currently being explored as an invaluable source for treatment of cancerous and infectious diseases. As of 2013, 1453 new chemical entities (NCEs) have been approved by the US FDA, of which 40% are NPs or NP-inspired (semi-synthetic NP derivatives, synthetic compounds based on NP pharmacophores, or NP mimics) [8, 9]. A number of NPs Such as alkaloids, flavonoids, terpenoids, polyketides, lignans, saponins, peptides and plant extracts exhibited potent anti-CML activity.
Alkaloids are naturally occurring organic compounds containing heterocyclic ring with nitrogen atom. Alkaloids, widely distributed in plant kingdom, are bitter secondary metabolites synthesized by plants, microbes and animals. They possess several physiological activities like anti-malarial, anti-asthmatic, anti-cancer, anti-bacterial, antiviral, anti-hyperglycemic and vasodilatory activities [10–13]. Their anti-CML activity is described below.
Berbamine (BBM) is a natural bisbenzylisoquinoline product, isolated from traditional Chinese herbal medicine Berberis amurensis, was tested on imatinib resistant K562 cell line (K562/IR) both in vitro and in vivo. The IC50 value was found to be 17.1 and 11.1 μM at 24 and 48 h. BBM downregulated Bcl-2, Bcl-xL, mdr-1 mRNA, p-gp levels and enhanced Bax & cytochrome C (cyt.C) release. BALB/c or nu/nu mice were injected with K562-r subcutaneously and the tumor-bearing mice, when treated with BBM [60 mg/kg body weight (BW)] intravenously effectively suppressed the xenotransplated tumors in these mice [14]. BBM also induced apoptosis in CML cells via downregulating survivin protein levels [15]. At 8 μg/ml dose of BBM, NFκB nuclear, IKK-α, IKB-α [16], BCR-ABL, p-BCR-ABL level were decreased [17]. Furthermore, BBM-induced differentiation of CML cells into RBC, granulocyte and megakaryocytes [18]. Interestingly, BBM is a heat shock protein 90 (Hsp90) inhibitor [19]. BBM inhibited MDR K562/adriamycin (ADR) [20] and K562/A02 cell lines consequently inducing apoptosis by reducing mdr-1 gene expression and reversing MDR effect [21]. 4-chlorobenzoyl berbamine (BBD9), an analogue of BBM was also tested against K562/IR. BBD9 with IC50 0.5 μg/ml was found to be more effective than BBM (IC50 8 μg/ml), BBD9-lowered BCR-ABL, IKK a, nuclear NF-κB. Furthermore, it increased the cleaved caspases 3,9, Poly(ADP-Ribose) polymerase (PARP) and LC3-phosphatidylethanolamine conjugate (LC3 II) expression levels. In nude mice model bearing K562 tumors, BBD9 was effective in reducing the tumor weight, promoting tumor regression [22]. E6, a derivative of BBM, was tested against MDR K562/doxorubicin (DOX) with 1, 3, 10 and 30 μM concentrations, and it significantly reduced the IC50 of DOX from 79.19 μM to 35.18, 21.86, 6.31 and 1.97 μM. Co-treatment of E6 with DOX arrested K562 cells at G2/M phase [23].
Camptothecin, isolated from Camptotheca acuminate, is documented to display anti-CML activity. Homocampthothecin (hCPT), a synthetic analogue of camptothecin, showed potent activity at IC50 value of 11 nM suggesting its potential use compared to parent compound camptothecin (IC50 57 nM) [24]. BN80927, an analogue of camptothecin, effectively inhibited K562 cell proliferation with IC50 of 8.4 nM [25]. NSC606985, an analogue of camptothecin, inhibited CML cell growth in a dose-dependent manner. The IC50 was found to be 6.25 nM [26]. Combination of imatinib and camptothecin increased Bax, cleavage of PARP-1, DNA-dependent protein kinase (DNA–PK) in CML cells [27].
Capsaicin, an active component of capsicum genus, is a homovanillic acid derivative experimentally is shown to exhibit anti-mutagenic activity [28]. Capsaicin treatment of K562 cells decreased microRNA (miRNA) expression such as miR-520a-5p, a putative target of STAT3. Hence, capsaicin induced apoptosis via reducing mRNA involved in JNK/STAT pathway [29]. Capsaicin also stimulated GATA-1 promoter in CML cells which is an essential transcriptional factor for the development of erythroid cells [30].
Homoharringtonine (HHT), isolated from Cephalotaxus harringtona, has been documented to inhibit CML cell proliferation in a dose-dependent manner. The IC50 was found to be 43.89 ng/ml. HHT arrested K562 cells at G0/G1 phase and, in addition, downregulated Bcl-2, NF-κB, p-JAK2, p-STAT5, p-Akt, p-BCR-ABL levels [31, 32].
Sanguinarine, a benzophenanthridine alkaloid, isolated from blood root plant Sanguinaria canadensis, belonging to the Papaveraceae family inhibited CML cell growth in a dose-dependent manner. At 1.5 μg/ml, sanguinarine induced apoptosis in CML cells. At higher concentration (12.5 μg/ml), sanguinarine caused blister formation in CML cells [33].
Staurosporine, an alkaloid isolated from the bacterium Streptomyces staurosporeus, not only inhibited CML cell growth but also induced differentiation of myeloid cell lineage to megakaryocytic lineage resulting in polypoidy formation. Staurosporine treatment resulted in upregulation and activation of JAK/STAT3, p-STAT3 nuclear translocation and downregulation of c-myc [34, 35]. Staurosporine also induced differentiation of CML cells into erythroid cells via increased CD61 and CD42b levels [36]. 7-Hydroxy staurosporine (UCN-01), a potent PKC inhibitor is effective in inhibiting CML cell proliferation at a concentration of 3 μM for 24 h [37, 38].
Tetrandrine is a bis-benzylisoquinoline alkaloid that is isolated from Chinese herb Stephania tetrandra. Combination of tetrandine and imatinib showed syngerisitic effect significantly inhibited CML cell growth. The combination treatment arrested CML cells at G1/S phase, enhanced caspase 3 mRNA, protein levels and decreased Bcl-2 mRNA, protein levels [39]. Combination of nilotinib and tetrandrine also effectively decreased the IC50 of daunorubicin (DNR) on K562/A02 to 3.12 ± 0.13 μg/ml. This combinational effect not only increased Bax mRNA and protein levels but also decreased the survivin mRNA and protein levels [40]. Tetrandrine citrate, a novel tetrandrine salt which is highly soluble in water, Inhibited the growth of K562/IR, primary leukemic cells and primitive CD34 (+) leukemic cells with IC50 ranging from 1.2 to 2.97 μg/ml. Tetrandrine citrate lowered BCR-ABL mRNA and β-catenin protein levels. Nude mice bearing CML tumors when orally administered with tetrandrine citrate (100 mg/kg BW), reduced the tumor growth [41]. Combination of 5-bromotetrandrine (analogue of tetrandrine) and DNR decreased p-JNK 11,2 and MDR/p-gp levels in ADR resistant K562 cells [42].
Alkaloids from plant and microbial source inhibited CML cell proliferation in micromole (μM)/microgram (μg) concentration (Table 1) (Figure 2) [43–66]. Alkaloids are well documented to potently reduce tumor growth in in vivo models (Table 2). Besides, some alkaloids such as capasaicin, staurosporine induces differentiation of CML cells (Table 3).
List of anti-CML alkaloids as 1—Ancistrotectorine E, 2—Berbamine, 3—BBD9, 4—Camptothecin, 5—BN80927, 6—NSC606985, 7—Homocamptothecin, 8—Capsaicin, 9—Cathachunine, 10—Cephranathine, 11—Crambescidin 800, 12—Crebanine, 13—Curine, 14—Cyanogramide, 15—9-deacetoxyfumigaclavine C, 16—d-Dicentrine, 17—Evodiamine, 18—Homoharringtonine, 19—Naamidine J, 20—Piperine, 21—Salvicine, 22—Staurosporine, 23—UCN-01, 24—Tetrandrine, 25—5-bromotetrandrine, 26—α-tomatine, 27—tylophorine, 28—tylophorinine, 29—5-chlorosclerotiamide, 30—10-episclerotiamide, 31—Eupolauramine, 32—Sampangine, 33, 34, 35—Arthpyrones A, B and C, 36–38—Auranomides A, B and C and 39—Virosecurinine.
Alkaloid | Source of isolation | IC50 value on K562 cells | Mechanism of action | References |
---|---|---|---|---|
Berbamine (bisbenzylisoquinoline alkaloid) | Berberis amurensis | 8 μg/ml | ↓Bcl-2, Bcl-xL, NFκB(nuclear), IKK-α, IKB-α, BCR-ABL, p-BCR-ABL, Hsp90 | [14–17] |
Camptothecin (quinoline alkaloid) | Camptotheca acuminate | 57 nM | ↑Bax, cleavage of PARP-1, DNA—PK adducts | [24] |
Homoharringtonine | Cephalotaxus harringtona | 43.89 ng/ml | ↓Bcl-2, NF-κB, p-JAK2, p-STAT5, p-Akt, p-BCR-ABL and ⊥G0/G1 phase | [31, 32] |
Sanguinarine (benzophenanthridine alkaloid) | Sanguinaria canadensis | – | At 1.5 μg/ml induced apoptosis | [33] |
Tetrandrine (bis-benzylisoquinoline alkaloid) | Stephania tetrandra | – | ↑Caspase 3 mRNA, protein and ↓Bcl-2 mRNA, protein | [39, 40] |
Ancistrotectorine E (napthylisoqunoline alkaloid) | 70% EtOH extract of Ancistrocladus tectorius | 4.18 μM | – | [43] |
1,2,3-Trimethoxy-5-oxonoraporphine and ouregidion (aporphine alkaloids) | Crude HEX, EtOAc and AQE extracts of Pseuduvaria rugosa (Blume) Merr | *63 and 64% | – | [44] |
Cathachunine | Catharanthus roseus (L.) G. Don | 9.3 ± 1.8 μM | – | [45] |
Cepharanthine | Stephania sp. | – | ↓p-gp | [46] |
Crebanine | Stephania venosa | 13 μg/ml | ↓Cyclin A, D & ↑Caspases 3,9,8 & PARP and ⊥G0/G1 phase | [48] |
Curine | Chondrodendron platyphyllum | 17.8 ± 5.2 μM | – | [49] |
Cyanogramide | Actinoalloteichus cyanogriseus WHI-2216-6 | – | At 5 μM, reversed MDR in K562/ADR | [50] |
9-Deacetoxyfumigaclavine C | Aspergillus fumigatus | 3.1 μM | – | [51] |
Evodiamine (quinazolinocarboline alkaloid) | Evodia rutaecarpa | 34.43 μM | – | [53] |
Naamidine J (imidazole containing alkaloid) | Pericharax heteroraphis | 11.3 μM | – | [54] |
Salvicine (diterpenoid alkaloid) | Salvia prioniti | 7.82 ± 2.81 μM | ⊥G1 phase | [56] |
Solamargine (glycoalkaloid) | Solanum species | 5.2 μM | ↑Caspases and ↓Bcl-2 | [57, 58] |
α-Tomatine (glycoalkaloid) | Solanum lycopersicum | 1.51 μM | Loss of MMP. ↑Bak, Mcl-1s, AIF and ↓survivin | [59] |
Tylophora alkaloids (tylophorine, tylophorinine, tylophorindine) | Tylophora indica | – | Nuclear condensation, ↑Caspases activation, release of cyt.C | [60] |
5-Chlorosclerotiamide and 10-episclerotiamide (prenylated indole alkaloids) | Aspergillus westerdijkiae DFFSCS013 | 44 and 53 μM | – | [61] |
Eupolauramine and sampangine (azaphenanthrene alkaloids) | Anaxagorea dolichocarpa Sprague and sandwith | 18.97 and 10.95 μg/ml | – | [62] |
Arthpyrones A, B and C (4-hydroxy-2-pyridone alkaloids) | Arthrinium arundinis ZSDS1-F3 | 0.24—45 μM | – | [63] |
Auranomides A, B and C | Penicillium aurantiogriseum | *20.48, 76.36 and 5.78% | – | [64] |
Malonganenones 1–3 (tetraprenylated alkaloids) | Euplexauria robusta | 0.35—10.82 μM | – | [65] |
Virosecurinine | Securinega suffruticosa | 32.984 μM | ↑PTEN & ↓mTOR, SHIP-2 BCR-ABL, and ⊥G1/S phase | [66] |
Anti-CML activity of alkaloids.
↑ ? upregulation, ↓ ? downregulation, ⊥ ? cell cycle arrest & * ? Inhibition rate (IR) at 100 ?g/ml.
Name of NP | Type of NP | Mice strain | Type of CML cells used to induce tumors | Dosage | Mode of administration | Mechanism of action | References |
---|---|---|---|---|---|---|---|
BBM | Alkaloid | Balb/c | K562-r | 60 mg/kg BW | Intravenously | ↓mdr-1 mRNA, p-gp protein | [14] |
BBD9 | Analogue of BBM | nu−/− | K562/IR | 15 and 30 mg/kg BW | – | ↓p-BCR-ABL, IKKa, NF-κBp65 | [22] |
Tetrandrine citrate | Alkaloid | nu−/− | K562/IR | 100 mg/kg BW | Orally | ↓BCR-ABL, β-catenin | [41] |
d-Dicentrine | Alkaloid | SCID | K562 | 100 mg/kg BW | Intraperitoneal | ↓tumor size | [52] |
Oroxylin A | Flavonoid | SCID | K562 | 80 mg/kg BW | Intravenously | ↓STAT3 pathway | [76] |
Nobiletin | Flavonoid | Nude mice | K562 | 12.5, 25, 50 mg/kg BW | – | ↓VEGF | [99] |
dEpoF | Polyketide | Nude mice | K562 | 6 mg/kg | Intravenously | Complete tumor regression | [147] |
HSS | Protein extract from Tegillarca granosa | – | K562/ADM | – | – | ↓mdr1, BCR-ABL and sorcin | [177] |
Gambogic acid | Garcinia hanburyi | Balb/c | KBM5-T315I | 3 mg/kg/2 days | Intraperitoneal | ↓Bcr-Abl, Akt, Erk1/2, and STAT5 | [229] |
TAF273 | Fraction of Eurycoma longifolia MeOH extract | Balb/c | K562 | 50 mg/kg | Intraperitoneal | ↑apoptosis and ↓blood vessel formation | [258] |
NPB001–05 | Piper betle extract | – | T315I | 500 mg/kg | Orally | ↓PI3K/AKT, MAPK pathways | [275] |
In vivo results of anti-CML NPs.
Name of NP | NP class | Differentiation of CML cells into | Mechanism of action | References |
---|---|---|---|---|
Capsaicin | Alkaloid | Erythroid cells | ↟GATA-1 promoter | [28–30] |
Staurosporine | Alkaloid | Megakaryocytes | ↟CD61, CD42b and ↓c-myc | [34–36] |
Crambescidin 800 | Alkaloid | Erythroblasts, induction of hemoglobin production | ⊥S-phase | [47] |
Piperine | Alkaloid | Macrophages/monocytes (20/40 μM) | – | [55] |
Apigenin | Flavonoid | Erythroid lineage | ↟ α and ϒ hemoglobin mRNA expression | [87] |
Galangin | Flavonoid | Monocytes | ↟CD61 | [90] |
Genistein | Flavonoid | Erythroid lineage | – | [92] |
EtOH extract of Olea europaea | Plant extract | Monocyte lineage | ↟CD14 | [243] |
EtOH extract of Stellera chamaejasme | Plant extract | Granulocytes | ↟CD11b | [250] |
Huangqi (Astragalus membranaceus) | Traditional Chinese medicine | Erythroid lineage | ↟β-globin gene expression | [272] |
List of some NPs and its differentiation capacity.
Flavonoids belong to polyphenolic compounds which are prevalent in plants. They contain two phenyl rings A, B and a heterocyclic ring C (commonly referred as C6-C3-C6 skeleton) and are classified into many major classes like flavones, flavonols, flavanones, flavanonols and isoflavonoids (Figure 3). They exhibit antioxidant, anti-inflammatory, anti-bacterial, antiviral and anti-cancer activities and play a significant role in human health [67–74].
Anti-CML activity of some NPs which include ? flavonoids: 1—Apigenin, 2—Baicalein, 3—Fistein, 4—Galangin, 5—Genistein, 6—Kaempferol, 7—Myricetin, 8—Naringenin, 9—Nobiletin, 10—Oroxylin A and 11—Tamarixetin. Terpenoids: 1—Gukulenin A, 2–4—Hebeiabinin A, D & E, 5—Parvifolines C, 6—3-hydrogenwadaphnin, 7—Tanshinone I, 8—EM23, 9, 10—Felixins F & G, 11—Kadlongilactone D. Polyketides: 1—Epiaspinonediol, 2—aza-EpoB, 3—dEpoF, 4—Heveadride, 5—Gilvocarin HE, 6—Rhizoxin, 7—Salarin C, 8—Tausalarin C, 9—Trineurone E. Lignans: 1—Arctigenin, 2—Cleistanthin A, 3—Honokiol, 4—6-hydroxyjusticidin C, 5—(+) –lariciresinol 9’-p-coumarate, 6—4-methoxy magndialdehyde. Peptides: 1, 2—chujamide A, B, 3—gombamide A.
Oroxylin A, an O-methylated flavone, found in the medicinal plant Scutellaria baicalensis, was tested against MDR K562/ADR cells. Oroxylin A specifically enhanced the sensitivity of K562/ADR to ADR by selectively inducing apoptosis. The treatment downregulated CXCR4 expression and inhibited PI3K/Akt/NF-κB pathways [75]. NOD/SCID mice-bearing K562 xenograft, treated with oroxylin A (30 mg/kg BW) alone or in combination with imatinib enhanced the sensitivity of imatinib to K562 cells through suppression of STAT3 pathway, decreasing p-gp levels thus reversing MDR in CML cells [76].
Quercetin (Q), a major flavonol, found in the kingdom Plantae, exhibits many biological effects including Antioxidant, anti-inflammatory, anti-cancer and anti-diabetic activities [77]. While evaluating the anti-proliferative effect of pytoestrogens, it was found that Q specifically inhibits K562 and MDR K562/A cell growth [78]. When K562 cells were treated with Q at a concentration of 9.2 mg/ml for 72 h, it induced apoptosis and reduced the BCR-ABL levels in CML cells [79]. Combination of Q and ADR was tested on MDR K562/ADR cells. Combined treatment enhanced activation of caspases 3,8 and loss of mitochondrial membrane potential (MMP). Furthermore, it lowered Bcl-2, Bcl-xl and enhanced the p-c-Jun-N terminal kinase and p-p38 mitogen-activated protein kinase (p-p38-MAPK). Q also significantly decreased the p-gp levels [80] and sensitized MDR K562/ADM to DNR and reversed MDR in CML cells [81]. Q inhibited K562 and MDR K562/A in the range of 5–160 μM. Q treatment of K562/ADR cells (5 μM) enhanced accumulation of ADR and, in addition, decreased the expression of MDR-causing proteins like ABC, solute carrier (SLC). Moreover, it reduced Bcl-2, TNF expression reversing MDR in CML cells [82]. Moreover, Q arrested CML cells at G2/M phase [83]. IC50 of Q on K562 and K562/ADR was found to be 11 ± 2 μM and 5 ± 0.4 μM [84]. It also inhibited the Hsp70 levels in CML cells [85]. Q induced apoptosis via inhibiting the telomerase enzyme by enhancing human telomerase reverse transcriptase (hTERT) enzymes in CML cells [86].
In sum, flavonoids not only inhibit the growth of CML cells (Table 4) but also induce their differentiation into erythroid or monocyte lineage (Table 3). Flavonoid fractions of plant extracts also inhibit CML cell proliferation and induced apoptosis [87–109].
Flavonoids/flavonoid fraction | IC50 value on K562 cells | Mechanism of action | References |
---|---|---|---|
Oroxylin A (o-methylated flavone) | – | ↓CXCR4, PI3K/Akt/NF-κB pathways | [75, 76] |
Quercetin (flavonol) | 11 ± 2 | Loss of MMP. ↑caspases 3,8 & ↓Bcl-2, Bcl-xl, Hsp70, telomerase and ⊥G2/M phase | [77–86] |
Apigenin (flavone) | – | ↓Mcl-1, Bcl-2 & ↑caspases activation and ⊥G2/M phase | [87, 91] |
Baicalein (flavone) | – | ↑ caspase 3, Fas gene and ⊥ S phase | [88] |
Fistein (flavonol) | – | Induced apoptosis and Altered JAK/STAT, KIT pathways and ⊥S & G2/M phases | [89, 97] |
Galangin (flavonol) | – | ↓pRb, cdk4, cdk1, cycline B & Bcl-2 levels and ⊥G0/G1 phase | [90] |
Kaempferol (flavonol) | – | ↟ Bax, SIRT3, caspases 3, 9 and ↓ Bcl-2 | [93] |
Myricetin (flavonol) | – | Myricetin pre-treatment enhanced Natural killer cells to kill K562 | [96, 97] |
Naringenin (flavanone) | – | ↟ p21/WAF1 and ⊥G0/G1 phase | [98] |
Tamarixetin (o-methylated flavonol) | – | ↟ cyclin B1, Bub1, p21, caspases and ↓tublin polymerization | [100] |
3,5-Dihydroxy-6,7,3′,4′-tetramethoxyflavone (DHTMF) (polymethoxyflavone) | 7.85 μg/ml | ↟caspases 3, 9 & PARP cleavage | [101] |
2″,3″-Diidroochnaflavone (Luxemburgia nobilis) | 89 μM | – | [102] |
Isochamaejasmin (biflavonoid) (Stellera chamaejasme L) | 24.51 ± 1.62 μM | ↟caspases 3, 9 and PARP cleavage | [103] |
Protoapigenone (total flavonoid fraction of Macrothelypteris torresiana) | 0.9 μg/ml | – | [104] |
Total flavonoids from Lysimachia clethroides Duby (ZE4) | – | ↓Bcl-2 and ↑Fas, TRAIL & DR5 | [105] |
Total flavonoids of Astragali Radix | 98.63 mg/L | ↓ cyclin D1 mRNA levels and ⊥G0/G1 phase | [106] |
Total oligomer flavonoids of Rhamnus alaternus | 196 μg/ml | – | [107] |
Flavonoid-enriched Rhamnus alaternus root and leaf extracts | 165 and 210.73 μg/ml | – | [108] |
Epigallocatechin-3-gallate (Camellia sinensis) | 50 μM | ↓CyclinD1, CDC25A and ↑TGF-β2 | [109] |
Anti-CML activity of flavonoids.
Terpenoids are naturally occurring products representing the largest secondary metabolites. Approximately 60% of NPs are terpenoids. They are basically made up of five carbon isoprene units (IU). Depending upon the number of isoprene units present, terpenoids has been classified into hemiterpenoids (1 IU), monoterpenoids (2 IU), sesquiterpenoids (3 IU), diterpenoids (4 IU), sesterterpenoids (5 IU), triterpenoids (6 IU), tetraterpenoids (8 IU) and polyterpenoid (n IU). They have been documented to possess antioxidant, anti-inflammatory, anti-helminitic and anti-cancer activities [110–115].
Sesquiterpenoids, diterpenoids, sesterterpenoids and triterpenoidshas been shown to potently inhibit CML cell proliferation and induce apoptosis (Figure 3) (Table 5) [116–144]. Other diterpenoids such as scapaundulin C (from Scapania undulate (L.) Dum.,) [120], parvifoline Z, parvifoline AA (from Isodon parvifolius) [121], labdane-type diterpenes (from Chloranthus henryi Hemsl.) [124] and sesterterpenoid compounds 3, 11 and 12 (from Sarcotragus sp.) [133] and triterpenoid compounds 1, 2, 5, 7 and 9 (from Ganoderma hainanense) [135], (24R/S)-24-hydroxy-3α 10α-epoxy-9-eip-cucurbita-25-ene (1a, b) (from Fructus Viticis Negundo) [136] are also shown to efficiently inhibit CML cell proliferation.
Terpenoid class | Name of terpenoid | Source of isolation | IC50 value on K562 cells | Mechanism of action | References |
---|---|---|---|---|---|
Sesquiterpenoids | EM23 | Elephantopus mollis | 10.8 μM | ↟ caspases, PARP cleavage and ↓ NFκB. Loss of MMP | [116] |
Diterpenoids | Caesalminaxin D and H | Caesalpinia minax | 9.9 ± 1.7 and 9.2 ± 0.9 μM | – | [117] |
Gukulenin A and diterpenoid pseudodimers (2–5) | Phorbas gukhulensis | *0.26 ± 0.03, 0.12 ± 0.01, 0.44 ± 0.01, 0.32 ± 0.05 and 0.04 ± 0.09 μM | – | [118] | |
Diterpene compounds 11, 12, 13, 14 and 15 | petroleum ether soluble fraction of the aerial parts of Tirpitzia ovoidea ethanol extract | 86.4, 66.3, 91, 45.1 and 58.6 μM | – | [119] | |
7β,11β,14β-Trihydroxy-ent-kaur-20-al-6,15-dioxo-16-ene | Isodon xerophilus | 0.04 μM | – | [122] | |
Hebeiabinin A, D and E | Isodon rubescens var. rubescens | 53.21, 5.05 and 0.91 μM | – | [123] | |
Parvifolines C | Isodon parvifolius | 13.8 μM | – | [125] | |
3-Hydrogenwadaphnin | Dendrostellera lessertii | 15 nM con. caused 45% apoptosis | – | [126] | |
Enanderianins K—P, Rabdocoetsin B and D | Isodon enanderianus | 0.13–0.87 μg/ml | – | [127] | |
Ludongnin J | Isodon rubescens var. lushiensis | 0.18 μg/ml | – | [128] | |
Tanshinone I | Salvia miltiorrhiza Bunge. | 38 ± 5.2 μM | ↟ Bax, caspase 3 and ↓Survivin | [129] | |
ent-Kaurane diterpenoids 11, 16, 17 and 20 | Isodon nervosus | 2.39, 4.11, 1.05 and 1.55 μM | [130] | ||
5-Episinuleptolideacetate | Sinularia species | 4.09 μg/ml | ↓c-ABL, Akt, NFκB | [144] | |
Sesterterpenoids | Felixins F and G | Ircinia felix | 1.27 and 19.9 μM | – | [131] |
Compounds 8, 9 | Smenospongia sp. | *0.11 and 0.97μ/ml | – | [132] | |
Two linear furanosesterterpenes | Smenospongia sp. | 3 and 31.6 μg/ml | – | [134] | |
Triterpenoids | 3β,21β,24-Trihydroxyserrat-14-en-24-(4′-hydroxybenzoate) | Palhinhaea cernua | 56.1 μg/ml | – | [137] |
L-Arabinopyranosyloleanolic acid | Garcinia hanburyi resin | 4.15 μM | – | [138] | |
Nortriterpenoids | Schisandra propinqua var. propinqua | >100 μM | – | [139] | |
Kadlongilactone D | Kadsura longipedunculata | 1.92 μM | – | [140] | |
Six triterpenes | fractions of Aceriphyllum rossii methanolic extract | 12.2—28.7 μM | – | [141] | |
Argetatin B | Parthenium argentatum | Cytotoxic at 5—25 μM con. | – | [142] | |
Celastrol (quinone methide triterpene) | Tripterygium wilfordii Hook F | – | ↓pSTAT5, p-CRKL, pERK1/2, p-Akt, p-BCR-ABL, Bcl-xL, Mcl-1, survivin, Hsp90 | [143] |
Anti-CML activity of terpenoids.
*LC50, lethal concentation.
Polyketides represent a large group of natural products that are produced by microorganisms and plants. These are secondary metabolites, derived by the repetitive condensation of acetate units or other short carboxylic acids catalyzed by multi-functional enzymes called polyketide synthases (PKSs) which is similar to fatty acid synthases [145]. Many polyketides suppress CML cell proliferation and induce apoptosis (Figure 3) (Table 6) [146–155].
Type of NP | Name of compound | Source of isolation | IC50 value on K562 | Mechanism of action | References |
---|---|---|---|---|---|
Polyketides | Epiaspinonediol | Aspergillus sp. 16–02–1 | 44.3 μg/mL | – | [146] |
Geldanamycin | Streptomyces Hygroscopicus | – | ↓c-Raf, Akt, BCR-ABL | [148] | |
Heveadride | Ascomycota Dichotomyces cejpii | 82.7 ± 11.3 μM | ↟ TNFα | [149] | |
Gilvocarin HE | Streptomyces sp. QD01–2 | 45 μM | – | [150] | |
Radicicol | Diheterospora chlamydosporia and Monosporium bonorden | – | ↓p-Raf1, p-BCR-ABL | [151] | |
Rhizoxin | Burkholderia rhizoxina | 5×10−7 μg/ml | – | [152] | |
Salarin C | Fascaplysinopis sp. | 0.1 μM | ↟ caspase 3 and 9 cleavage | [153] | |
Tausalarin C | Fascaplysinopis sp. | 1 μM | – | [154] | |
Trineurone E | Peperomia trineura | 26 μM | – | [155] | |
Lignans | Arctigenin | Asteraceae family | – | ↑Bax and ↓ Bcl-2 | [157] |
Cleistanthin A | Cleistanthus collinus (Rox B) | 0.4 μM | – | [158] | |
5,5′-Dimethoxylariciresinol-4′-O-β-D-glucoside (DMAG) | Mahonia | – | ↓IC50 of DOX from 34.93 to 12.51 μM | [159] | |
Honokiol | Magnolia officinalis Rend. Et wils. | 28.4 μM | – | [160] | |
6-Hydroxyjusticidin C | Justica procumbens | 43.9 ± 2.9 μM | ↟ROS levels, casapase 3 | [161] | |
(+)-Lariciresinol 9′-p-coumarate | Larix olgensis var.koreana. | 2.9 μg/ml | – | [162] | |
4-Methoxy magndialdehyde | Magnolia officinalis | 3.9 μg/ml | – | [163] | |
Saponins | Astrgorgiosides A, B, C (19-norand aromatized B ring bearing steroid aglycone) | Astrogor dumbea | 26.8—45.6 μM | – | [168] |
Wattoside G, H, and I (steroidal saponins) | Tupistra wattii Hook.F. | 35.67, 76.16 and 76.96 μM | – | [169] | |
Tenacissoside C (steroidal saponins) | Marsdenia tenacissima | 31.4 μM | ↓ cyclin D, Bcl-2, Bcl-xL and ↑caspases 3, 9, Bax and Bak | [170] | |
Compounds 14 and 15 (C21-steroidal pregnane sapogenins) | Cynanchum wilfordii roots | 6.72 μM | – | [171] | |
Total saponin content | Aralia Taibaiensis | – | Loss of MMP. ↑ Bax and ↓ Bcl-2 | [172] | |
Saponin rich fraction (GSE) | Gleditsia sinensis Lam. fruit extract | 18 ± 1.6 μg/ml | ↑ Bax and ↓ Bcl-2, PCNA | [173] | |
23-Hydroxybetulinic acid | Total saponin content of Pulsatilla chinensis (Bunge) Regel | – | ↟ Bax, caspase 3 cleavage and ↓ Bcl-2, survivin | [174] | |
Peptides | Chujamides A and B | Suberites waedoensis | *37 and 55.6 μM | – | [175] |
Gombamide A | Clathria gombawuiensis | *6.9 μM | – | [176] |
Anti-CML activities of polyketides, lignans, saponins and peptides.
*LC50—lethal concentation.
Lignans, natural compounds that are exclusively found in plants, are derived from amino acid phenyl alanine. They possess anti-oxidant and anti-cancer activities [156]. Various lignans effectively inhibit CML cell proliferation and induced apoptosis (Figure 3) (Table 6) [157–163].
Saponins are a diverse group of secondary metabolites widely distributed in the plant kingdom. They produce soap-like foam when shaken in aqueous solutions. Their structure comprise of triterpene or steroid aglycone and one or more sugar chains. They exhibit anti-cancer and anti-cholesterol activities [164, 165]. Various saponins inhibited CML cell proliferation (Table 6) [166–174].
Two peptides, chujamides A (1) and B (2), isolated from the marine sponge Suberites waedoensis inhibited K562 cell growth with LC50 values of 37 and 55.6 μM [175]. Another peptide, gombamide A (1), isolated from the marine sponge Clathria gombawuiensis inhibited CML cell proliferation with LC50 of 6.9 μM [176]. Haishengsu (HSS), a protein extract from Tegillarca granosa, when administered in mice-bearing MDR K562/ADM cell tumors inhibited tumor growth and downregulated mdr1 gene, BCR-ABL and sorcin [177]. HSS was also tested against MDR K562/ADR cells, and it induced apoptosis at 20 mg/l [178]. HSS also inhibited K562 cells at G0/G1 and S phase and lowered Bcl-2 and enhanced Bax levels (Figure 2) (Table 6) [179].
Other natural products such as acetylenic metabolites, betanin, bufadienolide, mamea a/ba, cryptotanshinone, bavachalcone, polyanthumin, cubebin, denbinobin, digallic acid, perforanoid A, β- and α-mangostin, parthenolide, perezone, polyphyllin D, squamocin, toxicarioside H, tripolide, woodfordin I and rhodexin A inhibited CML cell proliferation (Table 7) [180–230]. Moreover, many plant crude extracts enriched with NPs inhibited the CML cell proliferation and induced apoptosis (Table 8) [231–280].
Name of NP | Source of isolation | IC50 value on K562 cells | Mechanism of action | References |
---|---|---|---|---|
Acetylenic metabolites | Stelletta sp. | 43.5, 51.3 and 62.5 μg/ml | – | [180] |
Betanin (betacyanin pigment) | Opuntia ficus-indica | 40 μM | ↟ PARP cleavage, release of Cyt C and ↓ BCl-2. Loss of MMP | [182] |
Bufalin 3β-acrylic ester (Bufadienolide) | “Ch’an Su” | 6.83 nM | – | [183] |
3-Formylcarbazole, methylcarbazole-3-carboxylate and 2-methoxy-1-(3-methyl-buten-1-yl)-9H-carbazole-3-carbaldehyde | Clausena lansium (Lour.) Skeels | 20.48 ± 1.78, 26.5 ± 2.12 and 23.49 ± 1.85 μg/ml | – | [184] |
Toxicarioside F and G | Latex of Antaris toxicaria (Pers.) Lasch | – | – | [185] |
Pangelin and oxypeucedanin hydrate acetonide | Angelica dahurica | 8.6–14.6 μg/ml | – | [186] |
Mamea A/BA | Calophyllum brasiliense | 0.04–0.59 μM | – | [187, 188] |
Cryptotanshinone (lipid soluble active compound) | Salvia miltiorrhiza | – | induced apoptosis ↑ PARP cleavage and ↓BCR-ABL, STAT3, mTOR & eIF4E | [189, 190] |
Bavachalcone (Chalcones) | – | 2.7 μM | – | [191] |
Polyanthumin (novel chalcone trimmer) and sulfuretin | Memecylon polyanthum H.L. Li. | 45.4 and 30.5 μg/ml | – | [192] |
(−)-Cubebin | Piper cubeba | 8.66 ± 0.43 μM | – | [193] |
Denbinobin | 5-Hydroxy-3,7-dimethoxy-1,4-phenanthraquinone | 1.84 μM | ↓ BCR-ABL, CrkL and⊥G2/M phase | [194] |
Digallic acid | Pistascia lentiscus | – | Induced DNA fragmentation and pro-apoptotic effect in CML cells | [195] |
1,4,5-Trihydroxy-7-methoxy-9H-fluoren-9-one, dendroflorin and denchrysan (fluorenones) | Dendrobium chrysotoxum | 32.18, 26.65 and 52.28 μg/ml | – | [196] |
C27-Steroidal glycoside | Liriope graminifolia (Linn.) Baker | 18.6 μg/ml | – | [198] |
9α-Acetoxyartecanin, apressin, inducumenone and centaureidin | Achillea clavennae | 9.84 ± 2.52, 4.44 ± 0.76, 52.53 ± 8.43 and 5.37 ± 0.8 μM | – | [199] |
Perforanoid A (limonoid) | – | 4.24 μM | – | [200] |
Linoleic acid | Methanol extracts of proso and Japanese millet | 68 μM | – | [201] |
β- and α-Mangostin | Garcinia malaccensis | 0.40 μM and 0.48 μM | – | [202, 203] |
Nudifloside and linearoside (iridoid) | EtOH extract of the aerial parts of Callicarpa nudiflora Hook | 20.7 and 36 μg/ml | – | [204] |
Parthenolide | – | 17.1, 8.67 and 9.42 for 24, 48 and 72 h | Induced apoptosis | [205] |
Perezone | Perezia spp. | – | Cytotoxic to CML cells at 25, 50 and 100 μM and induced apoptosis | [206] |
Compound 6a (phenalenone metabolite) | Coniothyrium cereal | 8.5 μM | – | [207] |
Polyphyllin D | Paris polyphyllin | – | ↟ p21, Bax, caspase 3 & Cyt. C release and ↓ cyclin B1, cdk1, Bcl-2. Loss of MMP and ⊥ G2/M phase | [208] |
Polysaccharide (PSP001) | Punica granatum | 52.8 ± 0.9 μg/ml | – | [209] |
Riccardin F and Pakyonol (macrocyclic bisbenzyls) | Plagiochasm intermedium | 0–6 μg/ml | – | [210] |
Highly methoxylated bibenzyls | Frullania inouei | 11.3–49.6 μM | – | [211] |
Sarcovagine and β-sitosterol 5- 8 | Sarcococca saligna | 2.5–5 μM | – | [212] |
Squamocin (annonaceous acetogenins) | – | – | ↟ cdk inhibitors, p21, p27 & ↓ cdk1, cdk25c and ⊥G2/M phase | [213] |
Klyflaccisteroid J | Klyxum flaccidum | 12.7 μM | – | [214] |
Suvanine (N,N-dimethyl-1,3-dimethylherbipoline salt) and suvanine-lactam derivatives (4–8) | Coscinoderma sp. sponge | * 2.2, 1.9, 3.9, 4.6, 3.9 and 3.6 μM | – | [215] |
ar-Turmerone | Curcuma longa L | 20–50 μg/ml | Induced DNA fragmentation and apoptosis | [216] |
Terpene metabolites (1–3) | Clathria gombawuiensis | *4.7, 3.9 and 2.1 μM | – | [217] |
Toxicarioside H (nor-cardenolide) | Antiaris toxicaria (Pers.) Lesch | 0.037 μg/ml | – | [218] |
Tripolide | Chinese herbal extract | – | ↓ Nrf2 and HIF-1α mRNA and protein expression | [219] |
10-(Chrysophanol-7′-yl)-10-hydroxychrysophanol-9-anthrone and ramosin | Fractions of EtOH extract of Asphodelus microcarpus Salzm.et Vivi | 0.15 ± 0.02 and 0.65 ± 0.01 μM | – | [220] |
Withametelins I, J, K, L and N | MeOH extract of Datura metel flowers | 0.05, 2.5, 0.12, 0.55 and 0.46 μM | – | [221] |
Woodfordin I (macrocyclic ellagitannin dimer) | – | – | ↓ Bcl-2, Bcl-xL, Bax, c-Abl & BCR-ABL \nand Loss of MMP | [222] |
Gaudichaudic acid, isogambogenic acid and deoxygaudichaudione A (xanthones) | Garcinia hanburyi resin | 0.41 ± 0.03, 2.1 ± 0.14 and 1.74 ± 0.22 μg/ml | – | [223] |
Xindongnins C–D, A, B, melissoidesin G, dawoensin A and glabcensin V | Isodon rubescens var. rubescens | 0.3–7.3 μg/ml | – | [224] |
Hyperbeanols B and D | MeOH extract of Hypericum beanie | 16.9 and 20.7 μM | – | [225] |
Rhodexin A | Rhodea japonica | 19 nM | ⊥G2/M phase induced apoptosis | [226] |
Curcumin | Curcumina longa | 20 μg/ml | ↓BCR-ABL, Hsp90, WT1 | [227, 228] |
Gambogic acid | Garcinia hanburyi | 0.62 μM | ↓p-BCR-ABL, pSTAT5, p-CRKL, pERK1/2, p-Akt | [229, 230] |
Anti-CML activity of other natural products.
*LC50–lethal concentation.
Plant extract | IC50 value on K562 cells | Mechanism of action | References |
---|---|---|---|
Acetone extract of Peucedanum nebrodense (Guss.) Strohl., | 14–10.27 μg/ml | – | [231] |
AQE extract of Cornus officinalis Sieb. et Zuce | 100 μg/ml | – | [232] |
AQE extracts of the husk fiber of the typical A and common varieties of Cocos nucifera (Palmae) | At 500 μg/ml the cell viability of CML cells was found to be 60.1 ± 8.5 and 47.5 ± 11.9% | – | [233] |
AQE extract of Rhodiola imbricate | – | ↓CML cell proliferation at 100 and 200 μg/ml for 72 hrs. induced ROS & apoptosis and ⊥G2/M phase | [234] |
Abnobaviscum F® (standardized AQE extract of European mistletoe from the host tree Fraxinus) | – | ↟ caspase 9, JNK-1,2, p38 MAPK and ↓ Bcl-1, Erk-1/2 & PKB phosphorylation | [235] |
Chloroform extract of Polyalthia rumphii stem | 40–60μ/ml | – | [236] |
Chloroform extract of Tecomella undulata bark | 30 μg/ml | ↟ FAS, FADD, & caspase 8, 3/7. Induced DNA fragmentation & apoptosis | [237] |
DCM) extract of Psidium guajava L. | 32 μg/ml | – | [238] |
DCM extract Artemisia turanica Krasch | 69 μg/ml | ↟ caspases, PARP cleavage. Induced DNA damage and apoptosis | [239] |
HEX and DCM extract of Mesua beccariana | *20 ± 1.5 and 43.75 ± 0.78 μg/ml | – | [240] |
HEX and DCM extract of Mesua ferrea | *17.5 ± 1.02 and 22.91 ± 1.25 μg/ml | – | [240] |
HEX extract of Mesua congestiflora | 40.63 ± 1.45 μg/ml | – | [240] |
DCM fraction of Melissa officinalis | At 50 μg/ml concentration, it induced 65.04 ± 0.93% apoptotic rate | ↟ Fas, Bax mRNA levels and Bax/Bcl-2 ratio | [241] |
DCM fraction of the crude EtOH extract of Echinops grijissi Hance roots | 30 μg/ml | – | [242] |
EtOH extract of Pereskia sacharosa | 130 ± 0.03 μg/ml | ↟ caspases, cyt. C release, p21 & p53 and ↓Akt and Bcl-2 | [244] |
EtOH extract of propolis (NP produced by stingless bee Melipona orbignyi) | At 250 and 500 μg/ml promoted cell death of CML cells by 15 ± 1 and 63 ± 2% | – | [245] |
EtOH extract of Isodon japonicas | 2.7 μg/ml | – | [246] |
EtOH root extract of Allamanda schottii | At 800 μg/ml showed cytotoxicity | – | [247] |
EtOH stem and leaf extract of Physalis peruviana | 0.02 and 0.03 g/ml | – | [248] |
Alcoholic extract of Dendrostellera lessertii | 28 μl and 5 × 10−9M | – | [249] |
EtOH extract of Rosmarinus officinalis L | 1/400 dilution | – | [251] |
EtOH extract of Goldfussia psilostachys | 0.5 μg/ml | ↟ CML cells in G2/M phase | [252] |
Fraction from EtoAc of Caesalpinia spinosa | 44.5 ± 4.05 μg/ml | induced chromatin condensation. Loss of MMP & ↑ caspase 3 | [253] |
EtoAc extract of Helichrysum plicatum flowers | 25.9 μg/ml | – | [254] |
MeOH extract of Linum persicum | 0.1 μg/ml | – | [255] |
MeOH extracts of Echinophora cinerea and Cirsium bracteosum | Less than 20 μg/ml | – | [256] |
MeOH extract of Galium mite | 39.8 μg/ml | – | [256] |
MeOH extract of Cyperus rotundus | 175 ± 1.2 μg/ml | Induced DNA damage | [257] |
TAF273, F3 and F4 fractions of MeOH extract of Eurycoma longifolia Jack | 19, 55 and 62 μg/ml | – | [258] |
MeOH extract of Rhaphidophora korthalsii | – | Enhanced Natural killer cells to kill K562, ↟IFN-ϒ, TNF-α | [259] |
MeOH extract of Rhinella jimi Stevaux (Anura: Bufonidae) skin | *235 μg/ml | – | [260] |
MeOH extract of Hypericum perforatum L.flower extract | – | Induced apoptosis | [261] |
HEX, DCM, EtoAc, butanol and MeOH extracts of Helichrysum zivojinii Černjavski and Soška | 11.78 ± 0.94, 23.82 ± 6.54, 27.52 ± 4.96, 50.37 ± 3.28 and 74.88 ± 7.57 μg/ml (for 72 h) | – | [262] |
Acetate: MeOH (95:5), acetate, chloroform and HEX fractions of Erythroxylum caatingae plowman | 13.1 ± 0.63, 9.86 ± 0.56, 11.21 ± 0.46, 33.58 ± 1.33 μg/ml | – | [263] |
DCM extract of Arctium lappa root | ^17 μg/ml | – | [264] |
Alisma orientalis (Sam) Juzep extract | – | Reverse of MDR | [265] |
Polyphenolic extract of Ichnocarpus fructescens leaves | – | At 5, 10, 20 μg/ml con. ↓K562 cell proliferation | [266] |
EtOH extract of Orbignya speciosa | 33.9 ± 4.3 μg/ml | – | [267] |
Coptis chinensis and Epimedium sagittatum extracts | 29 and74 μg/ml | – | [268] |
Sangre de Drago is red viscous latex extract of Croton lechleri | 2.5 ± 0.3 μg/ml | – | [269] |
Dionysia termeana extract | 20 μg/ml | – | [270] |
Ganoderma lucidum extract | *50 μg/ml | – | [271] |
Crude MeOH extracts of Luehea candicans Mart. et Zucc. branches and leaves | #8.1–5.4 μg/ml | – | [273] |
Nerium oleander extract | – | ↓p-gp | [274] |
Ponicidin (Rabdosia rubescens extract) | – | ↓ Bcl-2 and ↑ Bax, caspase 3 & PARP cleavage | [276] |
Scutellaria litwinowii Bornm. and Sint. ex Bornm. | – | ↟ caspase 3,8, PARP cleavage, Bax/Bcl-2 ratio | [278] |
Swietenia mahagoni leaf extract | – | ↟ caspases 3,9, Cyt. C release and ⊥G2-M phase | [279] |
Viscin, (lipophilic extract from Viscum album L) | 252 ± 37 μg/ml | – | [280] |
Anti-CML activity of plant extracts.
AQE, aqueous, DCM, dichloromethane, HEX, hexane, EtOH, ethanol, EtoAc, ethyl acetate, MeOH, methanol, ^TGI, tumor growth inhibition,*ED50, –effective concentration; # GI50, growth inhibition.
Of the several natural products, Homoharringtonine (alkaloid) (NCT00114959) is currently under phase II study sponsored by Chem Genex pharmaceuticals to reverse the Gleevac resistance in CML patients [281]. 17-AAG (analogue of glendamycin–polyketide) (NCT00100997) is currently under phase I clinical trial sponsored by Jonsson Comprehensive Cancer Center collaborated with National Cancer Institute (NCI). Efforts are underway to determine the side effects and optimal dose of 17-AAG for treating patients with CML in chronic phase who did not respond to imatinib-mesylate [282]. Paclitaxel (diterpenoid) (NCT00003230) is currently under Phase I/II trials to study the effectiveness in treating patients with refractory or recurrent acute leukemia or CML. This work is sponsored by Swiss Group for Clinical Cancer Research [283].
CML is a hematological malignancy that arises due to chromosomal translocation resulting in the presence of Ph chromosome. Initially, TKIs were designed to compete with the ATP binding site of BCR-ABL. TKIs effectively inhibited wild-type BCR-ABL; however, mutations in BCR-ABL and overexpression of drug efflux proteins following treatment decreased their potency.
Since, there is a need for alternative strategy to develop new BCR-ABL inhibitors; NPs (obtaining from living organisms) offers an alternate, effective and inexpensive design for CML therapy. Moreover, they have less (or) no side effects. Studies conducted so far have revealed that many NPs inhibit CML cell proliferation and, in addition, induce cell death through apoptosis. NPs alone or in combination with other TKIs are able to reverse the MDR, thereby increasing the sensitivity of TKIs towards CML. Moreover, many NPs are able to differentiate CML cells into erythroid, monocyte or macrophage lineage. In vivo results have clearly shown that NPs potently suppress tumor growth. In sum, NPs serve as an inexhaustible source which renders an attractive alternate strategy to combat CML.
Conflict of interests
The authors declare that they do not have any competing interests.
Abbreviations
CML | chronic myeloid leukemia |
Ph | Philadelphia chromosome |
MAPK | mitogen activated protein kinase |
STAT | signal transducers and activator of transcription |
PI3K | phosphoinositide 3-kinase |
TKIs | tyrosine kinase inhibitor |
FDA | Food and Drug Administration |
MDR | multi drug resistance |
p-gp | p-glycoprotein |
NPs | natural products |
NCEs | new chemical entities |
BBM | berbamine |
K562/IR | imatinib resistant K562 cell line |
cyt. C | cytochrome C |
BW | body weight |
ADR | adriamycin |
Hsp90 | heat shock protein 90 |
BBD9 | 4-chlorobenzoyl berbamine |
PARP | Poly(ADP-Ribose) polymerase |
LC3 II | LC3-phosphatidylethanolamine conjugate |
DOX | doxorubicin |
hCPT | homocampthothecin |
DNA-PK | DNA-dependent protein kinase |
miRNA | microRNA |
HHT | homoharringtonine |
UCN-01 | 7-hydroxy staurosporine |
μM | micromole |
μg | microgram |
Q | quercetin |
DNR | daunorubicin |
MMP | mitochondrial membrane potential |
p-p38-MAPK | p-p38 mitogen-activated protein kinase |
SLC | solute carrier |
hTERT | human telomerase reverse transcriptase |
IU | isoprene units |
PKSs | polyketide synthases |
DMAG | 5,5′-dimethoxylariciresinol-4′-O-β-D-glucoside |
HJC | 6-hydroxyjusticidin C |
HSS | Haishengsu |
This chapter concerns the numerical simulation and the PIV measurements on oxy-fuel burners with three separated jets. The mixing, dynamic and the temperature fields for both reacting and non-reacting flows are investigated.
\nIndustrial systems with combustion phenomena such as burners, aeronautical engines and gas turbines are subject to increasingly important constraints, both economically (cost reduction, improved performance, etc.) than on the environmental level (reduction of pollutant emissions), requiring the development of new techniques to respond effectively to these industrial constraints. The development passes by new method of combustion in order to reduce pollutant emissions and fuel consumption, as well as by the improvement of flame stability [1, 2]. In previous studies, significant reductions of nitric oxide emissions have been successfully achieved by using low NOx technologies or oxy-combustion systems [3].
\nIn air combustion, nitrogen leads to high fuel consumption and low combustion efficiency because nitrogen in the air acts as energy ballast. The substitution of air with pure oxygen leads to an increase in the laminar combustion rate up to 1300%, improves the thermal efficiency, increases the adiabatic flame temperature (2200 K for CH4-Air, 3090 K in oxy-combustion) reduce fuel consumption by 50% and, from an environmental point of view, reduce the formation of nitrogen oxides by up to 95% [4].
\nThe flames from multiple jets aligned have used in many industrial installation. Several studies have been published on the dynamic properties of non-reacting multiple jets [5, 6, 7, 8, 9]. Lee et al. [10] have studied the geometry parameters of diffusion flames and giving a number of variables such as the number of jets and the distance between the jets. Lenze et al. [11] have studied the influence of three and five non-premixed flames, with town gas and natural gas burners. Their measurements concern flame width, flame length and concentrations in confined and free multiple flames.
\nA new generation of highly separated fuel and oxidant injection burners is of great interest to industrialists. The idea of this burner consists of separating combustible and oxidant to dilute the reactants with combustion products before the mixing of the reactants [12, 13, 14].
\nFor this new combustion in a burner with three separated jets, the separation of jets provides a high dilution of reactants by combustion products in the combustion chamber. Consequently, this dilution decreases the flame temperature and decline in NOx production. In the literature, it has been proven that the separation of reactants are capable to change the flow structure, the flame characteristics, generates a better thermal efficiency and as well as reduction of pollutant emissions [15, 16, 17, 18].
\nSalentey et al. [16] was interested in the characterization the flames from multiple jets aligned through dynamic properties (speed of the jets and distance injectors) and the flame topology (stability, length, blow ...). Lesieur et al. [14] has studied numerically the characteristics of a burner with three jets, focusing on the mixing of the jets, their dynamics and the pollutant emissions. Boushaki et al. [12] was interested on two main areas for flow, passive control with changing the diameter of the burner in order to affecting the dynamics flow; and active control requiring external energy intake through actuators while retaining the geometry of the combustion chamber.
\nThe present chapter reports the results of a numerical and experimental investigation of the dynamic field on a burner with 25 kW power composed of three jets, one central jet of natural gas and two side jets of pure oxygen [19, 20]. One control systems, passive, is added to the basic burner to ameliore the combustion process to ensure the stabilization of flame and as well as pollutant reductions. The passive control is based on the inclined of side oxygen jets towards the central natural gas jet in burner with three separated jets.
\nFew works, are investigated the effect of equivalence ratios (in lean regime) on characteristics of non-premixed oxy-methane flames from burner with separated jets. However, the aim of this contribution is to investigate numerically the effect of different equivalence ratio on the combustion characteristics of a diffusion methane oxy-flame in a stabilized separated burner.
\nThe mixture of hydrogen and natural gas is a new mixed fuel. The use of a mixed mixture of fuel and hydrogen has the advantage of modifying very effectively the properties of the fuel while preserving the distribution facility. Due to this, the high molecular diffusivity of hydrogen, the extended flammability limits, the high laminar flame speed and the low ignition energy, the addition of hydrogen in the fuel makes it possible to work in a combustion poor. Increasing flammability limits in the presence of hydrogen offset the adverse effects of poor combustion such as local extinctions, radiation energy losses, and flame stretching [21].
\nThe configuration of the burner illustrated in Figure 1 consists in separating the fuel and oxygen per injection in order to increase the dilution of the reactants with the combustion products before the mixing of the reagents.
\nSchematic view of the burner.
This burner consists of three non-ventilated jets, one central with internal diameter dg equal 6 mm that contains the fuel and two side jets with internal diameter dox equal 6 mm contain pure oxygen. Boushaki et al. [22] have studied this three-jet burner configuration. The separation distance between the jets (S) used is 12 mm. The gas density equal to 0.83 kg m−3 and the oxygen is supplied by liquid air with a purity of 99.5% with a density of 1.354 kg m−3 (at 1 atm and at 15° C). The thermal power (P) of the burner is equal to 25 kW, therefore the flow rate and the output speed of the natural gas are respectively mng = 0.556 g s−1 and Ung = 27.1 ms −1.
\nThe first study in this document is the control technique, consists in inclining the side oxygen jets towards the natural gas jet as shown in Figure 1. The angle of oxygen jets (ϴ) compared to the vertical direction varies from 0 to 30° (0, 10, 20, and 30°), however, we will present the effect of angle of the side oxygen jets on the dynamic fluid, for many detail you can see [12].
\nThe combustion is carried out inside a square chamber of 60 × 60 cm2 section and a height of 1 m. The side walls are water cooled and refractory lined inside the combustion chamber. a converging 20 cm high and a final section of 12 × 12 cm is placed at the end of the chamber to limit the entry of air from above. In order to allow optical access to all flame zones, six windows are provided in each face of the chamber.
\nThe Particle Image Velocimetry (PIV) was used as a measurement technique to characterize the experimental dynamic field. The PIV technique requires a laser sheet that clarifies the flow area studied a CCD camera, control equipment and an acquisition PC. The laser used is the Nd-YAG Bi-pulse with frequency 10 Hz and wavelength of 532 nm. The laser chain used is composed by a first divergent cylindrical lens and then by a second convergent spherical lens. The Mie signal emitted by the particles is collected by CCD camera of type a Lavision FlowMaster (12-bit dynamic and resolution 1280 × 1024 pixels).
\nThe steady equations for conservation of mass, momentum, energy and species have been used in this numerical simulation. The second order equations for turbulence kinetic energy \n
Here \n
where \n
\n\n
The Finite Eddy Dissipation Model (EDM) is used to simulate the turbulence/chemistry interaction. This model is based on the hypothesis that the chemical reaction is fast in relation to the transport processes of the flow.
\n\nTable 1 summarizes the volumetric flow rates, the velocities, Reynolds number respectively of methane and oxygen of equivalence ratio (0.7, 0.8 and 1).
\nConfiguration | \n\n\n | \n\n\n | \n\n\n | \n\n\n | \n\n\n | \n\n\n | \n
---|---|---|---|---|---|---|
Confi 1 | \n1 | \n0.767 | \n1.534 | \n27.13 | \n27.13 | \n12,272 | \n
Confi 2 | \n0.8 | \n0.767 | \n1.917 | \n27.13 | \n33.86 | \n12,272 | \n
Confi 3 | \n0.7 | \n0.767 | \n2.19 | \n27.13 | \n38.69 | \n12,272 | \n
Dynamic conditions of the burner.
Reynolds Number is defined by the following equation:
\nA global equivalence ratio can be defined as the molar ratio of methane and oxidant at the injection to molar ratio methane and oxidant in stoichiometric conditions, as:
\nwhere Q is the volumetric flow rate.
\nThe second numerical study in this document is the effect of hydrogen to dynamic of flame. One of the jet transports the fuel, natural gas + hydrogen, and the other the pure oxygen. The values of the flow rates of fuel and the exit velocities are regrouped in Table 2.
\nΦ =1 | \n|||||
---|---|---|---|---|---|
P=25 kW | \n|||||
\n | \n\n | \n\n\n | \n\n\n | \n\n\n | \n\n\n | \n
0% H2\n | \n0.49 | \n0 | \n2.07 | \n27.07 | \n27.06 | \n
20% H2\n | \n0.46 | \n0.012 | \n2.03 | \n31.3 | \n26.66 | \n
40% H2\n | \n0.40 | \n0.02 | \n1.98 | \n37.07 | \n25.9 | \n
Flow rates and exit velocities of fuels and oxygen.
We shall consider an overall irreversible reaction between methane/hydrogen and pure oxygen:
\n\n\n
\nTable 2 summarizes the parameters of this numerical study including methane, hydrogen and oxygen flow rates, velocities, percentage of hydrogen and equivalence ratio.
\nFluent 6.3.2 is used to solve the steady equations for conservation of mass, momentum, energy and species. The finite volume method is used with second order upwind. In fact, convergence criterion of residuals for energy equation and for all other equations equal respectively 10−6 and 10−3. The GAMBIT is used to construct the grid; the computational domain has been extended 100 cm in the axial direction and 30 cm in the radial direction. A total number of 28,700 quadrilateral cells were generated using non-uniform grid spacing to provide an adequate resolution near the jet axis and close to the burner where gradients were large.
\nThe axial velocity profile at the inlet, of the methane is supposed constant. At the axis of symmetry, \n
The mean velocity fields carried out by PIV in non-reacting flow are represented on Figure 2. From initial state where ϴ = 0° to inclined state where ϴ = 30°, the dynamic field changes with the change of flow structure. The jets fusion point becomes closer the burner by increasing of the slope of jets. The interaction of jets starts at about 15 mm for ϴ = 0°, at z = 25 mm for ϴ = 30°.
\nMean velocity fields for jet oxygen angle 0° and 30° (longitudinal velocity in color scale) in non-reacting flow.
\nFigure 3 shows the distribution of velocity and the current lines in the combustion chamber near the burner with different inclined jets of oxygen. In the part separating the different jets (dark blue), velocity is negative because of the recirculation of the jets. The existence of two zones of recirculation is observed with different directions of rotation, which explains the appearance of the negative velocity. It is noted on the one hand that the recirculation zone decreases with the increase of Ө from 0 to 20°. This is very remarkable near the jet of oxygen. On the other hand, it can be observed that the recirculation zones appear outside the jet of air (see the lines of currents). The perturbation of velocity distribution increases with the increase of Ө. This perturbation is accompanied by an acceleration of the combination of different jets and consequently a faster combustion reaction, which explains the increase in velocity with the increase of Ө.
\nVelocity distribution and current lines in the combustion chamber.
The distributions of the temperature in the combustion chamber with different inclined jets are represented in Figure 4. It is clear here that the flame exists in the mixing zone of methane and oxygen, which represents the reaction zone. This zone is modified with the variation of the angle Ө. If we assume that the length of the flame is defined by the red color of the flame distribution, we can conclude that the length of the flame decreases with the increase of the angle Ө from 0.44 m for an inclination of 0° to 0.29 m for an inclination of 20° of the jet of oxygen.
\nTemperature distribution in the combustion chamber.
\nFigure 5 represents the evolution of the axial temperature at y = 0 mm with different angles of injection Ө of the oxygen jets. Firstly, it is observed that the temperature increases by moving away from the burner to a maximum value and then begins to decrease. For example for Ө = 0° the temperature increases from 300 K near the burner up to 3500 K at a height of 380 mm. This zone of increase presents the mixing zone of the reactants methane/oxygen. The second zone is the reaction zone where the temperature reaches its maximum. The third zone is where the temperature gradually decreases and which presents the plume of the flame. The second interpretation is that the flame reaches its maximum faster while the angle of injection Ө increases. Indeed, the temperature reaches its maximum at a height of 390 mm for Ө = 0° by contrast, it reaches its maximum at 260 mm for Ө = 30°. This interpretation leads to conclude that the length of the flame decreases with the increase in the angle of the oxygen jets. This result is in good agreement with the result of Boushaki [22], which showed that the average flame length decreases when the angle of oxygen jets increases such that its value is about 500 mm for Ө = 0° and decreases until 220 mm for Ө = 30°.
\nAxial distribution profiles of temperature at y = 0 mm with variation of the angle Ө.
The radial profiles of the mean longitudinal velocity (U) at different section (x/D = 1.66, x/D = 8.33 and x/D = 16.66) and for three equivalence ratios are represented in Figure 6. A classical behavior of the multiple jets is found, one notices that the velocity profile presents maxima and minima corresponding to the three jets. In the initial zone (near the burner) each jet follows its own evolution, further downstream these velocity extremes begin to disappear to form a single maximum located in the middle of the inner mixing layer.
\nRadial profiles of longitudinal velocity at different positions from the burner.
Near the burner (x/D = 1.66) and for the three values of richness (Ф = 1, Ф = 0.8 and Ф = 0.7), we note that the velocity remains constant at the level of the central jet and it increases at the level of the lateral jet (jet of oxygen) with the decrease of the wealth. It should be noted that for Ф = 1 and Ф = 0.7 the mean longitudinal velocities are equal to 27 m/s and 38.57 m/s, mean velocity show an increase of 30%. In the case x/D = 16.66, the velocity profiles are slightly flattened, more open which improves the mixing of the reagents.
\nThe influence of the equivalence ratio on the longitudinal velocity U is significant less. From an aerodynamics point of view, the decrease of equivalence ratio modifies the longitudinal velocity of flow near to the burner but keep the flow velocity behavior in the combination zone.
\n\nFigure 7 shows, the radial profiles of the turbulence intensity, u′/U, on function to the equivalence ratio and on sections different, x/D = 1.66, 8.33 and 16.66. In the case x/D = 1.66 we see two peaks of fluctuations in u′ ‘of the order of 7 m/s, one at the center corresponding to the mixing layer of the central jet and one from the central jet corresponding to the mixture layer of side jet. These peaks of fluctuations fade along the flow with decreasing longitudinal velocity as the jets interpenetrate.
\nTurbulence intensity at different positions from the burner.
The distribution of the temperature in sections different inside the combustion chamber, is shown in Figure 8. In the near of the burner, the temperature present one peak with maximum value equal to 3000°C. For a richness equal to 1 (Ф = 1) the maximum temperature of the adiabatic flame is T = 3000 K and for a richness 0.7 the maximum temperature equals approximately T = 3300 K. Therefore, the peaks represent the zone of the reaction between the fuel and oxidant after mixing and the region between the peaks represents the area of the fuel which is not yet burned and the reaction takes place at the interface of jets between fuel and oxidant. At x/D = 8.33 and for three equivalence ratio the peak temperature is observed equal to 3200°C and the temperature profile keep constant. Far from the burner when the richness decreases, an increase in the temperature in the flame zone is observed from 3000 to 3500°C which makes it possible to improve the heat transfers and makes it possible to have a better thermal efficiency.
\nRadial profiles of temperature at different positions from the burner.
\nFigure 9 shows the longitudinal velocity field for different percentages of hydrogen. By comparing the four fields, the potential cone for three configurations with the addition of hydrogen percentages (\n
Longitudinal velocity field for 0% H2, 20% H2 and 40% H2.\n
\nFigure 10 illustrates the radial temperature profiles for multiple hydrogen percentages in the fuel mixture. This figure shows that the substitution of a fraction of methane with hydrogen promotes the increase of the flame temperature because the calorific value of this compound is much higher than that of methane. For example, the addition of 20% hydrogen increases the temperature 2500–3400 K (up to 900 K), and the addition of 60% hydrogen increases the temperature until 3700 K (1200 K more than in pure methane combustion).
\nRadial profiles of the temperature for 0% H2, 20% H2, 40% H2 and 60% H2.\n
In this chapter, a new combustion technique in a burner with three separated jets is used. The idea of this burner consists of separating combustible and oxidant to dilute the reactants with combustion products before the mixing of the reactants. This type of burner has a great interest for the industry and the sizing of these burners requires a good understanding of the mechanisms controlling the stabilization of the flame, the release of heat and the production of pollutants.
\nThe Particle Image Velocimetry PIV is the technique used in experimental study in non-reacting flow and reacting flow inside the combustion chamber. The Reynolds Average Navier-Stokes (RANS) method is used in this numerical simulation with Realizable k-ε as a turbulence closure model. The eddy dissipation model is applied to take into account the turbulence-reaction interactions.
\nThe passive control added to the basic of the burner is based on the inclined of side oxygen jets towards the central natural gas jet in burner with three separated jets. From ϴ = 0° to inclined state ϴ = 30°, the jets fusion point becomes closer the burner as well as the dynamic field changes. The result shows that the inclination of the jets affects significantly the flow field and consequently the flame behaviour.
\nThe effect of equivalence ratio and hydrogen on characteristics of a non-premixed oxy-methane flame from a burner with separated jets is studied in this document. The velocity fields with different equivalence ratio (0.7, 0.8 and 1) are presented. Near the burner a decrease in the equivalence ratio increases the injection velocity of the lateral jet and keeps a constant velocity in the central jet. For the turbulence intensity, near and far from the burner, an increase in the turbulence intensity is observed in the two layers of internal mixtures, this makes it possible to improve the mixing and increase the stability of the flame. Thus, there is an increase in the adiabatic temperature of the flame, which promotes heat transfer and improves thermal efficiency.
\nThe use of hydrogen solves instability problems of the flame that are related to lean combustion, due to the high diffusivity and reactivity of hydrogen in combustion. The results showed that the addition of hydrogen increased the flame velocity and the temperature while reducing CO2 and CO emissions due to the reduction of the carbon in the fuel.
\n\n Tube internal tube, mm mass flow rate, kg.s−1\n natural gas jet thermal power, W Reynolds number separation distance between the jets, mm nozzle exit velocity of gas, m.s−1\n nozzle exit velocity of oxygen, m.s−1\n longitudinal mean velocity, m.s−1\n longitudinal velocity fluctuation, m.s−1\n radial mean velocity, m.s−1\n radial velocity fluctuation, m.s−1\n radial and longitudinal coordinate, mm dynamic viscosity, kg.m.s−1\n gas density, kg.m−3\n percentage of hydrogen transport terms equivalence ratio transport coefficient
Authors are listed below with their open access chapters linked via author name:
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\\n\\n\\n\\n\\n\\n\\n\\n\\n\\nJocelyn Chanussot (chapter to be published soon...)
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\\n\\nAbdul Latif Ahmad 2016-18
\\n\\nKhalil Amine 2017, 2018
\\n\\nEwan Birney 2015-18
\\n\\nFrede Blaabjerg 2015-18
\\n\\nGang Chen 2016-18
\\n\\nJunhong Chen 2017, 2018
\\n\\nZhigang Chen 2016, 2018
\\n\\nMyung-Haing Cho 2016, 2018
\\n\\nMark Connors 2015-18
\\n\\nCyrus Cooper 2017, 2018
\\n\\nLiming Dai 2015-18
\\n\\nWeihua Deng 2017, 2018
\\n\\nVincenzo Fogliano 2017, 2018
\\n\\nRon de Graaf 2014-18
\\n\\nHarald Haas 2017, 2018
\\n\\nFrancisco Herrera 2017, 2018
\\n\\nJaakko Kangasjärvi 2015-18
\\n\\nHamid Reza Karimi 2016-18
\\n\\nJunji Kido 2014-18
\\n\\nJose Luiszamorano 2015-18
\\n\\nYiqi Luo 2016-18
\\n\\nJoachim Maier 2014-18
\\n\\nAndrea Natale 2017, 2018
\\n\\nAlberto Mantovani 2014-18
\\n\\nMarjan Mernik 2017, 2018
\\n\\nSandra Orchard 2014, 2016-18
\\n\\nMohamed Oukka 2016-18
\\n\\nBiswajeet Pradhan 2016-18
\\n\\nDirk Raes 2017, 2018
\\n\\nUlrike Ravens-Sieberer 2016-18
\\n\\nYexiang Tong 2017, 2018
\\n\\nJim Van Os 2015-18
\\n\\nLong Wang 2017, 2018
\\n\\nFei Wei 2016-18
\\n\\nIoannis Xenarios 2017, 2018
\\n\\nQi Xie 2016-18
\\n\\nXin-She Yang 2017, 2018
\\n\\nYulong Yin 2015, 2017, 2018
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\n\n\n\n\n\n\n\n\n\nJocelyn Chanussot (chapter to be published soon...)
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nYuekun Lai
\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\n\nPrevious years (alphabetically by surname)
\n\nAbdul Latif Ahmad 2016-18
\n\nKhalil Amine 2017, 2018
\n\nEwan Birney 2015-18
\n\nFrede Blaabjerg 2015-18
\n\nGang Chen 2016-18
\n\nJunhong Chen 2017, 2018
\n\nZhigang Chen 2016, 2018
\n\nMyung-Haing Cho 2016, 2018
\n\nMark Connors 2015-18
\n\nCyrus Cooper 2017, 2018
\n\nLiming Dai 2015-18
\n\nWeihua Deng 2017, 2018
\n\nVincenzo Fogliano 2017, 2018
\n\nRon de Graaf 2014-18
\n\nHarald Haas 2017, 2018
\n\nFrancisco Herrera 2017, 2018
\n\nJaakko Kangasjärvi 2015-18
\n\nHamid Reza Karimi 2016-18
\n\nJunji Kido 2014-18
\n\nJose Luiszamorano 2015-18
\n\nYiqi Luo 2016-18
\n\nJoachim Maier 2014-18
\n\nAndrea Natale 2017, 2018
\n\nAlberto Mantovani 2014-18
\n\nMarjan Mernik 2017, 2018
\n\nSandra Orchard 2014, 2016-18
\n\nMohamed Oukka 2016-18
\n\nBiswajeet Pradhan 2016-18
\n\nDirk Raes 2017, 2018
\n\nUlrike Ravens-Sieberer 2016-18
\n\nYexiang Tong 2017, 2018
\n\nJim Van Os 2015-18
\n\nLong Wang 2017, 2018
\n\nFei Wei 2016-18
\n\nIoannis Xenarios 2017, 2018
\n\nQi Xie 2016-18
\n\nXin-She Yang 2017, 2018
\n\nYulong Yin 2015, 2017, 2018
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