Mitochondria-Targeted Photoinduced Anticancer Activity of Oxidovanadium( IV) Complexes of Curcumin in Visible Light

Oxidovanadium(IV) complexes VO(py-aebmz)(B)]Cl (1, 2) and VO(napth-py-aebmz)(cur)]Cl 3; py-aebmz = 2-(1H-benzimidazol-2-yl)-N-(pyridin-2-ylmethylene)ethanamine, HB = acetylacetone (Hacac, 1) and curcumin (Hcur, 2), napth-py-aebmz = naphthalimide conjugated to py-aebmz ] have been prepared, characterized and their photoinduced DNA cleavage activities and photocytotoxicities studied. Complexes 1-3 each exhibited an irreversible cyclic voltammetric response of the V-IV/V-III redox couple at around -0.85 V versus SCE in dmf/0.1 M tbap. The complexes showed DNA photocleavage activity in visible light of 454, 530 and 647 nm through hydroxyl radical and singlet oxygen pathways. Fluorescence microscopy data suggest mitochondrial localization of complex 3 bearing a naphthalimide with a two-fold increase in photocytotoxicity in HaCaT cells with an IC50 value of 6.3 M and a three-fold increase in MCF-7 cells with an IC50 of 5.4 M compared with complex 2. Both 2 and 3 were non-toxic in the dark.

Mitochondria targeting Photocytotoxic Oxidovanadium( IV) Complexes of Curcumin and ( Acridinyl) dipyridophenazine in Visible Light

Oxidovanadium(IV) complexes, VO(acac)(L)Cl] (1), VO(cur)(L)Cl] (2), and VO(scur)(L)Cl] (3) {acac = acetylacetonate, cur = curcumin monoanion, scur = diglucosylcurcumin monoanion, L = 11-(9-acridinyl)dipyrido3, 2-a:2',3'-c]phenazine (acdppz)}, were prepared and characterized. The complexes are non-electrolytic in DMF and 1:1 electrolytic in aqueous DMF. The one-electron paramagnetic complexes showed a d-d band near 725 nm in aqueous DMF and green emission near 520 nm in aqueous DMSO. The complexes exhibited an irreversible V-IV/V-III redox response near -0.85 V versus SCE in aqueous DMF. The complexes showed good binding strengths to calf thymus DNA (K-b: 3.1x10(5)-9.6x10(5) M-1) and efficient pUC19 DNA photocleavage activity in red light of 705 and 785 nm by singlet oxygen (O-1(2)) pathway. Complexes 1 and 2 exhibited significant photocytotoxicity (IC50: 0.1-1.0 M) in visible light (400-700 nm) with low dark toxicity (IC50: >20 M) in HeLa and HaCaT cells. Complex 3 was cytotoxic in both light and dark. DNA ladder formation experiments indicated cell death via apoptotic pathway. Confocal microscopy done with 1 and 2 revealed primarily cytosolic localization of the complexes with significant presence of the complex in the mitochondria as evidenced from the imaging data using mitotracker red.

Oxovanadium(IV) complexes of curcumin for cellular imaging and mitochondria targeted photocytotoxicity

Oxovanadium(IV) complexes VO(R-tpy)(cur)](ClO4) (1, 2) of curcumin (Hcur) and terpyridine ligands (R-tpy) where R is phenyl (phtpy in 1) or p-triphenylphosphonium methylphenyl bromide (C6H4CH2PPh3Br) (TPP-phtpy in 2) were prepared and characterized and their DNA photocleavage activity, photocytotoxicity and cellular localization in cancer cells (HeLa and MCF-7) were studied. Acetylacetonate (acac) complexes VO(R-tpy)(acac)](ClO4) of phtpy (3) and TPP-phtpy (4) were prepared and used as the control species. These complexes showed efficient cleavage of pUC19 DNA in visible light of 454 nm and near-IR light of 705 rim. Complexes 1 and 2 showed significant photocytotoxicity in visible light of 400-700 nm. FACS analysis showed sub-G1/G0 phase cell-cycle arrest in cancer cells when treated with 1 and 2 in visible light in comparison with the dark controls. Fluorescence microscopic studies revealed specific localization of the p-triphenylphosphonium complex 2 in the mitochondria of MCF-7 cancer cells whereas no such specificity was observed for complex 1.

Photoactivated cytotoxicity of ferrocenyl-terpyridine oxovanadium(IV) complexes of curcuminoids

Oxovanadium(IV) complexes, viz. VO(Fc-tpy)(Curc)](ClO4) (1), VO(Fc-tpy)(bDHC)](ClO4) (2), VO(Fc-tpy)(bDMC)](ClO4) (3) and VO(Ph-tpy)(Curc)](ClO4) (4), of 4'-ferrocenyl-2,2':6',2 `'-terpyridine (Fc-tpy) and 4'-phenyl-2,2':6',2 `'-terpyridine (Ph-tpy) and monoanionic curcumin (Curc), bis-dehydroxycurcmin (bDHC) and bis-demethoxycurcumin (bDMC) were prepared, characterized and their photo-induced DNA cleavage activity and photocytotoxicity in visible light studied. The ferrocenyl complexes 1-3 showed an intense metal-to-ligand charge transfer band near 585 nm in DMF and displayed Fc(+)/Fc and V(IV)/V(III) redox couples near 0.65 V and -1.05 V vs. SCE in DMF-0.1 M TBAP. The complexes as avid binders to calf thymus DNA showed significant photocleavage of plasmid DNA in red light of 647 nm forming (OH)-O-center dot radicals. The complexes showed photocytotoxicity in HeLa and Hep G2 cancer cells in visible light of 400-700 nm with low dark toxicity. ICP-MS and fluorescence microscopic studies exhibited significant cellular uptake of the complexes within 4 h of treatment with complexes. The treatment with complex 1 resulted in the formation of reactive oxygen species inside the HeLa cells which was evidenced from the DCFDA assay. (C) 2014 Elsevier Masson SAS. All rights reserved.

Photocytotoxic oxovanadium(IV) complexes of ferrocenyl-terpyridine and acetylacetonate derivatives

Oxovanadium(IV) complexes VO(Fc-tpy)(acac)](ClO4) (1), VO(Fc-tpy)(nap-acac)](ClO4) (2), VO(Fc-tpy)(py-acac)](ClO4) (3) and VO(Ph-tpy)(py-acac)](ClO4) (4) of 4'-ferroceny1-2,2':6',2 `'-terpyridine (Fc-tpy) and 4'-phenyl-2,2':6',2 `'-terpyridine (Ph-tpy) having monoanionic acetylacetonate (acac), naphthylacetylacetonate (nap-acac) or pyrenylacetylacetonate (py-acac) ligand were prepared, characterized and their photocytotoxicity in visible light studied. The ferrocenyl complexes 1-3 showed an intense charge transfer band near 585 nm in DMF and displayed Fc(+)/Fc and V(IV)/V(III) redox couples near 0.66 V and -0.95 V vs. SCE in DMF-0.1 M TBAP. The complexes as avid binders to calf thymus DNA showed significant photocleavage of plasmid DNA in green light (568 nm) forming center dot OH radicals. The complexes that are photocytotoxic in HeLa and MCF-7 cancer cells in visible light (400-700 nm) with low dark toxicity remain nontoxic in normal fibroblast 3T3 cells. ICP-MS and fluorescence microscopic studies show significant cellular uptake of the complexes. Photo-irradiation of the complexes causes apoptotic cell death by ROS as evidenced from the DCFDA assay. (C) 2015 Elsevier Masson SAS. All rights reserved.

Photoinduced DNA Crosslink Formation by Dichloridooxidovanadium(IV) Complexes of Polypyridyl Bases

Oxidovanadium(IV) complexes VO(pyphen)Cl-2] (1) and VO(pydppz)Cl-2] (2), where pyphen is 2-(2-pyridyl)-1,10-phenanthroline and pydppz is 3-(pyridin-2-yl)dipyrido3,2-a:2,3-c]phenazine, show remarkable photoinduced DNA crosslinking ability and photocytotoxicity. The complexes are non-electrolytes in DMF, 1:1 electrolytes in 20% aqueous DMF, and 1:2 electrolytes in 20% aqueous DMF upon photoirradiation with visible light of 400-700 nm. The paramagnetic complexes, which have one unpaired electron, show a d-d band near 780 nm in aqueous DMF. The IR data suggest a V=O moiety trans to a V-N bond. Complex VO(pydppz)Cl-2] (2), as a novel photoinducible nuclear ds-DNA crosslinking agent, shows visible-light-induced cytotoxicity in HeLa and MCF-7 cancer cells by an apoptotic pathway, giving IC50 values of 0.87 +/- 0.07 and 1.4 +/- 0.2 M, respectively, while being essentially nontoxic (IC50 > 40 M) in the dark and less toxic in normal MCF-10A cells.

Endoplasmic reticulum targeting tumour selective photocytotoxic oxovanadium(IV) complexes having vitamin-B6 and acridinyl moieties

Oxovanadium(IV) complexes of vitamin-B6 Schiff base, viz., VO(HL1/L-2/L-3)(B)] Cl (1-4), where B is 2,2'-bipyridine (bpy in 1 and 2), 11-(9-acridinyl)dipyrido3,2-a:2',3'-c]phenazine (acdppz in 3 and 4), H2L1 center dot HCl is 3-hydroxy-5-(hydroxymethyl)-4-(((2-hydroxyphenyl)imino)methyl)-2-methylp yridin-1-ium chloride (in 1 and 4), HL2 is 2-(((2-(1H-imidazol-4-yl)ethyl) imino)methyl) phenol (in 2) and HL3 is 4-(((2-(1H-imidazol-4- yl)ethyl)imino)methyl)-5-(hydroxymethyl)-2-methylpyridin-3-ol (in 3) were synthesized, characterized and their cellular uptake, photo-activated cytotoxicity and intracellular localization were studied. Complexes 1a, as the perchlorate salt of 1, and 2a, as the hexafluorophosphate salt of 2, were structurally characterized. Vitamin-B6 transporting membrane carrier (VTC) mediated entry into tumour cells in preference to the normal ones seems to be responsible for the higher cellular uptake of the complexes into HeLa and MCF-7 cells over MCF-10A cells. Complexes 3 and 4 having acdppz as the photosensitizer exhibit remarkable photocytotoxicity in these cancer cells giving IC50 of < 0.9 mu M. The complexes remain non-toxic in the dark. The complexes show photo-induced apoptotic cell death via singlet oxygen (O-1(2)) generation. Fluorescence microscopy reveals specific localization of complex 4 to endoplasmic reticulum (ER) and generation of O-1(2) possibly leads to apoptotic cell death by triggering ER stress response (ERSR).

Endoplasmic reticulum targeting tumour selective photocytotoxic oxovanadium(IV) complexes having vitamin-B6 and acridinyl moieties

Oxovanadium(IV) complexes of vitamin-B6 Schiff base, viz., VO(HL1/L-2/L-3)(B)] Cl (1-4), where B is 2,2'-bipyridine (bpy in 1 and 2), 11-(9-acridinyl)dipyrido3,2-a:2',3'-c]phenazine (acdppz in 3 and 4), H2L1 center dot HCl is 3-hydroxy-5-(hydroxymethyl)-4-(((2-hydroxyphenyl)imino)methyl)-2-methylp yridin-1-ium chloride (in 1 and 4), HL2 is 2-(((2-(1H-imidazol-4-yl)ethyl) imino)methyl) phenol (in 2) and HL3 is 4-(((2-(1H-imidazol-4- yl)ethyl)imino)methyl)-5-(hydroxymethyl)-2-methylpyridin-3-ol (in 3) were synthesized, characterized and their cellular uptake, photo-activated cytotoxicity and intracellular localization were studied. Complexes 1a, as the perchlorate salt of 1, and 2a, as the hexafluorophosphate salt of 2, were structurally characterized. Vitamin-B6 transporting membrane carrier (VTC) mediated entry into tumour cells in preference to the normal ones seems to be responsible for the higher cellular uptake of the complexes into HeLa and MCF-7 cells over MCF-10A cells. Complexes 3 and 4 having acdppz as the photosensitizer exhibit remarkable photocytotoxicity in these cancer cells giving IC50 of < 0.9 mu M. The complexes remain non-toxic in the dark. The complexes show photo-induced apoptotic cell death via singlet oxygen (O-1(2)) generation. Fluorescence microscopy reveals specific localization of complex 4 to endoplasmic reticulum (ER) and generation of O-1(2) possibly leads to apoptotic cell death by triggering ER stress response (ERSR).

Oxalato complexes of oxovanadium (IV)

Oxalato oxovanadium (IV) complexes with neutral ligand molecules like dimethyl sulphoxide (DMSO) and antipyrine (Apy), VOOX·2DMSO and VOOX·2Apy and complex oxalates of oxovanadium (IV)-(NH4)2[VOOX2]·2H2O, (NH4)2[(VO)2OX3]·6H2O and (NH4)2[(VO)2OX3] have been prepared and characterized by different methods. In the divanadyl complexes, V-V and V-O-V-O types of bonding are shown to be absent by magnetic and spectral data and a bridged oxalato group co-ordinated to the two vanadium atoms is shown to be present, in addition to the usual bidentate oxalate groups. The possible stereochemical arrangements are indicated for the complexes.

Photocytotoxicity and near-IR light DNA cleavage activity of oxovanadium(IV) Schiff base complexes having phenanthroline bases

Oxovanadium(IV) complexes VO(L)(B)] (1-3), where H2L is a Schiff base ligand 2-(2-hydroxybenzylideneamino) phenol and B is 1,10-phenanthroline (phen for 1), dipyrido3,2-d:2',3'-f]quinoxaline (dpq for 2) or dipyrido3,2-a:2',3'-c]phenazine (dppz for 3), have been prepared, characterized and their DNA binding property and photo-induced DNA cleavage activity studied. Complex 3 which is structurally characterized by X-ray crystallography shows the presence of an oxovanadium(IV) moiety in a six coordinate VO3N3 coordination geometry. The complexes show a d-d band within 800-850 nm in DMF. The complexes display an oxidative response near 0.7 V versus SCE for V(V)-V(IV) and a reductive response within -1.1 to -1.3 V due to V(IV)-V(III) couple in DMF-0.1 M TBAP. The complexes are avid binders to calf thymus DNA giving binding constant values of 4.2 x 10(4) to 1.2 x 10(5) M (1). The complexes do not show any ``chemical nuclease'' activity in dark. The dpq and dppz complexes are photocleavers of plasmid DNA in UV-A light of 365 nm via O-1(2) pathway and in near-IR light (752.5 to 799.3 nm IR optics) by HO* pathway. Complex 3 exhibits significant photocytotoxicity in visible light in HeLa cells giving IC50 value of 13 mu M, while it is less toxic in dark (IC50 = 97 mu M). (C) 2010 Elsevier B.V. All rights reserved.

Synthesis, X-ray structures, and spectroscopic and electrochemical properties of (mu-oxo)bis(mu-carboxylato)diruthenium complexes having six imidazole bases as terminal ligands

Complexes [Ru2O(O2CR)(2)(1-MeIm)(6)](ClO4)(2) (la-c), [Ru2O(O2CR)(2)(ImH)(6)](ClO4)(2) (2a,b), and [Ru2O(O2CR)(2)(4-MeImH)(6)](ClO4)(2) (3a,b) with a (mu-oxo)bis(mu-carboxylato)diruthenium(III) core have been prepared by reacting Ru2Cl(O2CR)(4) with the corresponding imidazole base, viz. 1-methylimidazole (1-MeIm), imidazole (ImH), and 4-methylimidazole (4-MeImH) in methanol, followed by treatment with NaClO4 in water (R: Me, a; C6H4-p-OMe, b; C6H4-p-Me, c). Diruthenium(III,IV) complexes [Ru2O(O2CR)(2)(1-MeIm)(6)](ClO4)(3) (R: Me, 4a; C6H4-p-OMe, 4b; C6H4-p-Me, 4c) have been prepared by one-electron oxidation of 1 in MeCN with K2S2O8 in water. Complexes la, 2a . 3H(2)O, and 4a . 1.5H(2)O have been structurally characterized. Crystal data for the complexes are as follows: la, orthorhombic, P2(1)2(1)2(1), a = 7.659(3) Angstrom, b = 22.366(3) Angstrom, c = 23.688(2) Angstrom, V = 4058(2) Angstrom(3), Z = 4, R = 0.0475, and R-w = 0.0467 for 2669 reflections with F-o > 2 sigma(F-o); 2a . 3H(2)O, triclinic, , a = 13.735(3) Angstrom, b = 14.428(4) Angstrom, c = 20.515(8) Angstrom, alpha = 87.13(3)degrees, beta = 87.61(3)degrees, gamma = 63.92(2)degrees, V = 3646(2) Angstrom(3), Z = 4, R = 0.0485 and R-w = 0.0583 for 10 594 reflections with F-o > 6 sigma(F-o); 4a . 1.5H(2)O triclinic, , a = 11.969(3) Angstrom, b = 12.090(6) Angstrom, c = 17.421(3) Angstrom, alpha = 108.93(2)degrees, beta = 84.42(2)degrees, gamma = 105.97(2)degrees, V = 2292(1) Angstrom(3), Z = 2, R = 0.0567, and R-w = 0.0705 for 6775 reflections with F-o > 6 sigma(F-o). The complexes have a diruthenium unit held by an oxo and two carboxylate ligands, and the imidazole ligands occupy the terminal sites of the core. The Ru-Ru distance and the Ru-O-oxo-Ru angle in la and 2a . 3H(2)O are 3.266(1), 3.272(1) Angstrom and 122.4(4), 120.5(2)degrees, while in 4a . 1.5H(2)O these values are 3.327(1) Angstrom and 133.6(2)degrees. The diruthenium(III) complexes 1-3 are blue in color and they exhibit an intense visible band in the range 560-575 nm. The absorption is charge transfer in nature involving the Ru(III)-d pi and O-oxo-p pi orbitals. The diruthenium(III,IV) complexes are red in color and show an intense band near 500 nm. The diruthenium(III) core readily gets oxidized with K2S2O8 forming quantitatively the diruthenium(III,IV) complex. The visible spectral record of the conversion shows an isosbestic point at 545 nm for 1 and at 535 nm for 2 and 3. Protonation of the oxide bridge by HClO4 in methanol yields the [Ru-2(mu-OH)(mu-O2CR)(2)](3+) core. The hydroxo species shows a visible band al 550 nm. The pK(a) value for la is 2.45. The protonated species are unstable. The 1-MeIm species converts to the diruthenium(III,IV) core, while the imidazole complex converts to [Ru(ImH)(6)](3+) and some uncharacterized products. Complex [Ru(ImH)(6)](ClO4)(3) has been structurally characterized. The diruthenium(III) complexes are essentially diamagnetic and show characteristic H-1 NMR spectra indicating the presence of the dimeric structure in solution. The diruthenium(III,IV) complexes are paramagnetic and display rhombic EPR spectral features. Complexes 1-3 are redox active. Complex 1 shows the one-electron reversible Ru-2(III)/(RuRuIV)-Ru-III, one-electron quasireversible (RuRuIV)-Ru-III/Ru-2(IV), and two-electron quasireversible Ru-2(III)/Ru-2(II) couples near 0.4, 1.5, and -1.0 V vs SCE In MeCN-0.1 M TBAP, respectively, in the cyclic and differential pulse voltammetric studies. Complexes 2 and 3 exhibit only reversible Ru-2(III)/(RuRuIV)-Ru-III and the quasireversible (RuRuIV)-Ru-III/Ru-2(IV) couples near 0.4 and 1.6 V vs SCE, respectively, The observation of a quasireversible one-step two-electron transfer reduction process in 1 is significant considering its relevance to the rapid and reversible Fe-2(III)/Fe-2(II) redox process known for the tribridged diiron core in the oxy and deoxy forms of hemerythrin.

Mitochondria-Targeting Oxidovanadium(IV) Complex as a Near-IR Light Photocytotoxic Agent

Oxidovanadium(IV) complexes VO(L-1)(phen)]Cl (1) and VO(L-2)(L-3)]Cl (2), in which HL1 is 2-{(benzimidazol-2-yl)methylimino]-methyl}phenol (sal-ambmz), HL2 is 2-({1-(anthracen-9-yl)methyl]-benzimidazol-2-yl}methylimino)-met hyl]phenol (sal-an-ambmz), phen is 1,10-phenanthroline and L-3 is dipyrido3,2-a:2,3-c]phenazine (dppz) conjugated to a Gly-Gly-OMe dipeptide moiety, were prepared, characterized, and their DNA binding, photoinduced DNA-cleavage, and photocytotoxic properties were studied. Fluorescence microscopy studies were performed by using complex 2 in HeLa and HaCaT cells. Complex 1, structurally characterized by X-ray crystallography, has a vanadyl group in VO2N4 core with the VO2+ moiety bonded to N,N-donor phen and a N,N,O-donor Schiff base. Complex 2, having an anthracenyl fluorophore, showed fluorescence emission bands at 397, 419, and 443nm. The complexes are redox-active exhibiting the V(IV)/V(III) redox couple near -0.85V versus SCE in DMF 0.1M tetrabutylammonium perchlorate (TBAP). Complex 2, having a dipeptide moiety, showed specific binding towards poly(dAdT)(2) sequence. The dppz-Gly-Gly-OMe complex showed significant DNA photocleavage activity in red light of 705nm through a hydroxyl radical ((OH)-O-.) pathway. Complex 2 showed photocytotoxicity in HaCaT and HeLa cells in visible light (400-700nm) and red light (620-700nm), however, the complex was less toxic in the dark. Fluorescence microscopy revealed the localization of complex 2 primarily in mitochondria. Apoptosis was found to occur inside mitochondria (intrinsic pathway) caused by ROS generation.

Remarkable Selectivity and Photo-Cytotoxicity of an Oxidovanadium(IV) Complex of Curcumin in Visible Light

Oxidovanadium(IV) complexes of 2-(2'-pyridyl)-1,10-phenanthroline (pyphen), viz. VO(pyphen)(acac)](ClO4) (1), VO(pyphen)(anacac)](ClO4) (2) and VO(pyphen)(cur)](ClO4) (3), where acac is acetylacetonate (in 1), anacac is anthracenylacetylacetonate (in 2) and cur is curcumin monoanion (in 3) were synthesized, characterized and their photo-induced DNA cleavage activities and photo-cytotoxicities studied. The complexes are 1: 1 electrolytes in DMF. The one-electron paramagnetic complexes show a d-d band near 760 nm in DMF. Complexes 2 and 3 are blue and green emissive, respectively, in DMSO. The complexes exhibit irreversible V-IV/V-III reductive responses near -1.1 V and V-V/V-IV oxidative responses near 0.85 V vs. SCE in DMF-0.1 M TBAP. Complexes 2 and 3 display significant and selective photo-cytotoxicity upon irradiation with visible light giving an IC50 value of about 5 mu M against HeLa and MCF-7 cancer cells; they are significantly less-toxic against normal 3T3 control cells and in the absence of light. Complex 1 was used as a control. Both cytosolic and nuclear localization of the complexes were observed on the basis of fluorescence imaging. The complexes, avid binders to calf thymus (ct) DNA, were found to photocleave supercoiled pUC19 DNA upon irradiation with near-IR light (785 nm) by generating hydroxyl radical (OH) as the reactive oxygen species (ROS). Cell death events noted with HeLa and MCF-7 cell lines likely are attributable to apoptotic pathways involving light-assisted generation of intracellular ROS.

Remarkable enhancement in photocytotoxicity and hydrolytic stability of curcumin on binding to an oxovanadium(IV) moiety

Oxovanadium(IV) complexes of polypyridyl and curcumin-based ligands, viz. VO(cur)(L)Cl] (1, 2) and VO(scur)(L)Cl] (3, 4), where L is 1,10-phenanthroline (phen in 1 and 3), dipyrido3,2-a:2',3'-c]phenazine (dppz in 2 and 4), Hcur is curcumin and Hscur is diglucosylcurcumin, were synthesized and characterized and their cellular uptake, photocytotoxicity, intracellular localization, DNA binding, and DNA photo-cleavage activity studied. Complex VO(cur)(phen)Cl] (1) has (VN2O3Cl)-N-IV distorted octahedral geometry as evidenced from its crystal structure. The sugar appended complexes show significantly higher uptake into the cancer cells compared to their normal analogues. The complexes are remarkably photocytotoxic in visible light (400-700 nm) giving an IC50 value of <5 mu M in HeLa, HaCaT and MCF-7 cells with no significant dark toxicity. The green emission of the complexes was used for cellular imaging. Predominant cytosolic localization of the complexes 1-4 to a lesser extent into the nucleus was evidenced from confocal imaging. The complexes as strong binders of calf thymus DNA displayed photocleavage of supercoiled pUC19 DNA in red light by generating (OH)-O-center dot radicals as the ROS. The cell death is via an apoptotic pathway involving the ROS. Binding to the VO2+ moiety has resulted in stability against any hydrolytic degradation of curcumin along with an enhancement of its photocytotoxicity.

A glucose-centric perspective of hyperglycemia

Digestion of food in the intestines converts the compacted storage carbohydrates, starch and glycogen, to glucose. After each meal, a flux of glucose (>200 g) passes through the blood pool (4-6 g) in a short period of 2 h, keeping its concentration ideally in the range of 80-120 mg/100 mL. Tissue-specific glucose transporters (GLUTs) aid in the distribution of glucose to all tissues. The balance glucose after meeting the immediate energy needs is converted into glycogen and stored in liver (up to 100 g) and skeletal muscle (up to 300 g) for later use. High blood glucose gives the signal for increased release of insulin from pancreas. Insulin binds to insulin receptor on the plasma membrane and activates its autophosphorylation. This initiates the post-insulin-receptor signal cascade that accelerates synthesis of glycogen and triglyceride. Parallel control by phos-dephos and redox regulation of proteins exists for some of these steps. A major action of insulin is to inhibit gluconeogensis in the liver decreasing glucose output into blood. Cases with failed control of blood glucose have alarmingly increased since 1960 coinciding with changed life-styles and large scale food processing. Many of these turned out to be resistant to insulin, usually accompanied by dysfunctional glycogen storage. Glucose has an extended stay in blood at 8 mM and above and then indiscriminately adds on to surface protein-amino groups. Fructose in common sugar is 10-fold more active. This random glycation process interferes with the functions of many proteins (e.g., hemoglobin, eye lens proteins) and causes progressive damage to heart, kidneys, eyes and nerves. Some compounds are known to act as insulin mimics. Vanadium-peroxide complexes act at post-receptor level but are toxic. The fungus-derived 2,5-dihydroxybenzoquinone derivative is the first one known to act on the insulin receptor. The safe herbal products in use for centuries for glucose control have multiple active principles and targets. Some are effective in slowing formation of glucose in intestines by inhibiting alpha-glucosidases (e.g., salacia/saptarangi). Knowledge gained from French lilac on active guanidine group helped developing Metformin (1,1-dimethylbiguanide) one of the popular drugs in use. One strategy of keeping sugar content in diets in check is to use artificial sweeteners with no calories, no glucose or fructose and no effect on blood glucose (e.g., steviol, erythrytol). However, the three commonly used non-caloric artificial sweetener's, saccharin, sucralose and aspartame later developed glucose intolerance, the very condition they are expected to evade. Ideal way of keeping blood glucose under 6 mM and HbAlc, the glycation marker of hemoglobin, under 7% in blood is to correct the defects in signals that allow glucose flow into glycogen, still a difficult task with drugs and diets.