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(Very long article with a lot of references on the role of iron in many diseases, very interesting; complete on link)
https://link.springer.com/article/10.1007%2Fs00204-010-0577-x
(snip)
Iron deposition and disease: cause or effect? The case of atherosclerosis
I have implied that the role of unliganded iron is causative of a variety of sequelae, but sometimes this is hard to infer as the networks in which iron is involved are multiple and complex (hence the need for a systems approach—see later), and often simple one-time snapshots of covariates do not permit the inference of causality. However, one effect of the reaction of hydroxyl radicals (their formation catalysed by unliganded iron) with proteins (or lipids) is to tend to make those proteins (or lipids) insoluble or fibrotic (Davies 2005; Fig. 6), and if one believes that this is causative, the presence of insoluble plaques should correlate with the presence of the iron that is seen to have caused their formation and thereby became entrapped (and may yet be further reactive). Because of its biomedical importance, considerable work has been performed on atherosclerotic lesions, which provide a very clear example.
Atherosclerosis is a progressive (and inflammatory) disease (Altman 2003; Binder et al. 2002; Blake and Ridker 2001; Duewell et al. 2010; Dwyer et al. 2004; Forrester 2002, 2004; Gieseg et al. 2009; Grainger 2007; Hansson 2001, 2005; Himmelfarb et al. 2002; Kibel et al. 2008; Kunsch and Medford 1999; Libby 2002; Libby et al. 2002; Madamanchi et al. 2005a, b; Mullenix et al. 2005; Nigro et al. 2006; Packard and Libby 2008; Paoletti et al. 2004; Popa et al. 2007; Rader and Daugherty 2008; Ridker et al.et al. 2004; Ross 1999; Schleicher and Friess 2007; Subramanian and Ferrante 2009; Sullivan 2009; Tan and Lip 2008; Tang et al. 2009; Taqueti et al. 2006; Tedgui and Mallat 2006; van Leuven et al. 2008; van Oostrom et al. 2004; Willerson and Ridker 2004; Young et al. 2002) characterized by the accumulation of both oxidised lipids and various fibrous elements in arteries, often as plaques (Lusis 2000; Stocker and Keaney 2004). Several lines of evidence point to the involvement of iron in these processes:
Both iron and oxidised lipids (de Valk and Marx 1999; Smith et al. 1992) are found in atherosclerotic lesions (Altamura and Muckenthaler 2009; Brewer 2007; Chau 2000; Fernandes de Godoy et al. 2007; Gajda et al. 2008; Halliwell 2009; Horwitz et al. 1998; Kazi et al. 2008; Lee et al. 1998; McRae et al. 2009; Rajendran et al. 2007; Ramakrishna et al. 2003; Roijers et al. 2005; Smith et al. 1992; Stadler et al. 2004; Stanley et al. 2006; Stocker and Keaney 2005; Sullivan 2009; Watt et al. 2006; Wolff et al. 2004; Yuan and Li 2008)
Iron depletion by dietary or other means delays the formation of such lesions (Ferrara and Taylor 2005; Halliwell 2009; Lee et al. 1999; Matthews et al. 1997; Ponraj et al. 1999; Ren et al. 2005).
There is a correlation between iron status and atherosclerosis (Ahluwalia et al. 2010; Chau 2000; Day et al. 2003; de Valk and Marx 1999; DePalma et al. 2010; Gozzelino et al. 2010; Howes et al. 2000; Kallianpur 2005; Kartikasari et al. 2009; Kiechl et al. 1997; Lapenna et al. 2007; Marx et al. 2008; McRae et al. 2009; Minqin et al. 2003; Ramakrishna et al. 2003; Ren et al. 2003; Salonen et al. 1992; Shah and Alam 2003; Sullivan 2007, 2009; You et al. 2003; You and Wang 2005; Zacharski et al. 2000; Zacharski and Gerhard 2003) (and zinc is protective only against subsequent calcification, Stadler et al. 2008)
Exogenous ferric iron is deleterious to endothelial function (Rooyakkers et al. 2002)
Iron chelation improves endothelial function (Altamura and Muckenthaler 2009; Duffy et al. 2001; Halliwell 2009; Ishizaka et al. 2005; Saito et al. 2005; Thomas et al. 2006).
Iron levels in plaques correlate with the amount of oxidised proteins therein (Stanley et al. 2006); indeed in one study (Stadler et al. 2004), the EPR-detectable iron (essentially Fe(III)) in atherosclerotic tissue was seventeen times greater than that in the equivalent healthy tissue. I redraw these data in Fig. 7.
It seems clear that the application of similar studies to other diseases in which plaque formation occurs will be of benefit. Indeed, the location of iron in plaques has also been observed, for instance, for Alzheimer’s (e.g. Collingwood et al. 2008; Connor et al. 1992; El Tannir El Tayara et al. 2006; Ghribi et al. 2006; Haacke et al. 2005; Lovell et al. 1998; Morgan et al. 2004; Quintana 2007; Quintana et al. 2006; Sayre et al. 2000b; Schrag et al. 2009), ALS (Leveugle et al. 1997), MS (Haacke et al. 2009) and Parkinson’s (see above).
(snip)(Natural treatments)
Dietary or nutritional/nutraceutical
In addition, many organisms make so-called ‘secondary’ or natural products, whose functions are often unclear but that clearly have evolutionary benefits for the host (Hadacek et al. 2010; Kell et al. 1995). As I also reviewed (Kell 2009a), many iron-chelating natural products exist in (or may be added to, Pócsi et al. 2008) foodstuffs for which no full pharmaceutical regulatory controls are required and which are classed as nutritional substances. Many are polyphenols (ChEBI 26195) (Amic et al. 2007; Arts and Hollman 2005; Auclair et al. 2009; Cemeli et al. 2009; Cheynier 2005; Geronikaki and Gavalas 2006; Halliwell 2007; Jovanovic and Simic 2000; Kandaswami and Middleton 1994; Kiokias et al. 2008; Korkina and Afanas’ev 1997; Linseisen and Rohrmann 2008; Loke et al. 2009; Manach et al. 2004, 2005a, b; Pérez-Jiménez et al. 2010; Perron and Brumaghim 2009; Perron et al. 2008; Petti and Scully 2009; Pietta 2000; Rice-Evans and Packer 2003; Scalbert et al. 2005; Scalbert and Williamson 2000; Seifried et al. 2007; Slemmer et al. 2008; Spencer et al. 2008; Yadav and Bhatnagar 2007a, b, 2010), including the anthocyanins that proved chemoprotective (Butelli et al. 2008) in a mouse p53 cancer model. Since the previous review (Kell 2009a), I would draw particular attention to a comprehensive overview of the subject (Perron and Brumaghim 2009), as well as new reviews and papers on the chief polyphenol in green tea, (−)epigallocatechin-3-gallate (ChEBI 4806) (Adhami et al. 2009; Butt and Sultan 2009; Hsieh et al. 2009; Jimenez-Del-Rio et al. 2010; Johnson et al. 2010; Pandey and Gupta 2009; Paterniti et al. 2009; Ramesh et al. 2009; Reznichenko et al. 2010; Suh et al. 2009; Weinreb et al. 2009a), on curcumin (ChEBI 3962) (a constituent of turmeric) (Aggarwal and Harikumar 2009; Aggarwal and Sung 2009; Anand et al. 2010; Basile et al. 2009; Epstein et al. 2009; Hegde et al. 2009; Iqbal et al. 2009; Jiao et al. 2009; Jurenka 2009; Kalpravidh et al. 2010; Majumdar et al. 2009; Messner et al. 2009; Patil et al. 2009; Ravindran et al. 2009; Rivera-Espinoza and Muriel 2009; Thephinlap et al. 2009; Thomas et al. 2009; Tuntipopipat et al. 2009; Wang et al. 2009a), on eugenol (ChEBI 4917) (Nagababu et al. 2010) (and cf. Allen and Cornforth 2009), on nepetoidin caffeic acid esters (Maioli et al. 2010), on quercetin (ChEBI 16243) (Chobot 2010; Kitagawa et al. 2009; Krukoski et al. 2009; Lorrain et al. 2010; Park et al. 2010; Pavlica and Gebhardt 2010; Smirnova et al. 2009; Terao 2009; Vlachodimitropoulou et al. 2010) and on melatonin (CHEBI 16796) (Borah and Mohanakumar 2009; Korkmaz et al. 2008, 2009; Reiter et al. 2009; Sener et al. 2009; Sharma and Haldar 2009; Signorini et al. 2009). Many of the protective effects observed are likely due to the iron chelating, as well as directly antioxidative (redox) properties of these molecules (e.g. Ferrali et al. 1997a; Hague et al. 2006; Halliwell 2009; Halliwell et al. 2005; Hider et al. 2001; Končić et al. 2010; Lopes et al. 1999; Mandel et al. 2004; Mandel and Youdim 2004; Morel et al. 1994; Nijveldt et al. 2001; Rice-Evans et al. 1997; Rice-Evans and Packer 2003; Weinreb et al. 2007, 2009a; Yoshino and Murakami 1998). Other molecules that are not themselves directly antioxidant, but have iron-binding characteristics, may also be of benefit. This is certainly true of phytic acid (phytate; myo-inositol-1,2,3,4,5,6-hexakis phosphate; CHEBI 17401) (Aljandali et al. 2001; Allen and Cornforth 2009; Brune et al. 1989; Davidsson et al. 1994; Doria et al. 2009; Glahn et al. 2002; Graf and Eaton 1990, 1993; Graf et al. 1987; Grases et al. 2001; Hallberg et al. 1989; Han et al. 1994; Hanson et al. 2006; Hawkins et al. 1993; Kamp et al. 1995a, b, 2002; Kim et al. 2008; Kumar et al. 2010; Minihane and Rimbach 2002; Miyamoto et al. 2000; Panduri et al. 2006; Poser et al. 2004; Rao et al. 1991; Rimbach et al. 2008; Sandberg et al. 1999; Schlemmer et al. 2009; Shamsuddin 1995; Vucenik and Shamsuddin 2006; Xu et al. 2008).
Phlebotomy
In addition, as follows implicitly from Sullivan’s ‘iron hypothesis’ (Sullivan 1981, 2001, 2003, 2004) (and see Kell 2009a), one way to decrease the amount of iron in the body is to remove it by blood-letting or phlebotomy. While phlebotomy is a very traditional nostrum, often assumed or considered to have rather dubious or at best modest scientific support, there is in fact increasing literature implying its benefits in a variety of conditions (e.g. Aigner et al. 2008; Beutler 2007; Broedbaek et al. 2009; Brudevold et al. 2008; Busca et al. 2010; DePalma et al. 2007, 2010; Dereure et al. 2008; Desai et al. 2008; Dwyer et al. 2009; Equitani et al. 2008; Facchini et al. 2002; Fargion et al. 2002; Fernández-Real et al. 2002; Fujita et al. 2009; Fujita and Takei 2007; Hayashi et al. 2006; Hayashi and Yano 2002; Heathcote 2004; Horwitz and Rosenthal 1999; Hua et al. 2001; Kaito 2007; Kaito et al. 2006; Kato et al. 2001, 2007; Kom et al. 2006; Rajpathak et al. 2009; Sullivan 2009; Sumida et al. 2009; Tanaka et al. 2007, 2009; Toyokuni 2009b; Zacharski et al. 2008). Plausibly such benefits are due to its role in decreasing iron stores.
https://link.springer.com/article/10.1007%2Fs00204-010-0577-x
(snip)
Iron deposition and disease: cause or effect? The case of atherosclerosis
I have implied that the role of unliganded iron is causative of a variety of sequelae, but sometimes this is hard to infer as the networks in which iron is involved are multiple and complex (hence the need for a systems approach—see later), and often simple one-time snapshots of covariates do not permit the inference of causality. However, one effect of the reaction of hydroxyl radicals (their formation catalysed by unliganded iron) with proteins (or lipids) is to tend to make those proteins (or lipids) insoluble or fibrotic (Davies 2005; Fig. 6), and if one believes that this is causative, the presence of insoluble plaques should correlate with the presence of the iron that is seen to have caused their formation and thereby became entrapped (and may yet be further reactive). Because of its biomedical importance, considerable work has been performed on atherosclerotic lesions, which provide a very clear example.
Atherosclerosis is a progressive (and inflammatory) disease (Altman 2003; Binder et al. 2002; Blake and Ridker 2001; Duewell et al. 2010; Dwyer et al. 2004; Forrester 2002, 2004; Gieseg et al. 2009; Grainger 2007; Hansson 2001, 2005; Himmelfarb et al. 2002; Kibel et al. 2008; Kunsch and Medford 1999; Libby 2002; Libby et al. 2002; Madamanchi et al. 2005a, b; Mullenix et al. 2005; Nigro et al. 2006; Packard and Libby 2008; Paoletti et al. 2004; Popa et al. 2007; Rader and Daugherty 2008; Ridker et al.et al. 2004; Ross 1999; Schleicher and Friess 2007; Subramanian and Ferrante 2009; Sullivan 2009; Tan and Lip 2008; Tang et al. 2009; Taqueti et al. 2006; Tedgui and Mallat 2006; van Leuven et al. 2008; van Oostrom et al. 2004; Willerson and Ridker 2004; Young et al. 2002) characterized by the accumulation of both oxidised lipids and various fibrous elements in arteries, often as plaques (Lusis 2000; Stocker and Keaney 2004). Several lines of evidence point to the involvement of iron in these processes:
Both iron and oxidised lipids (de Valk and Marx 1999; Smith et al. 1992) are found in atherosclerotic lesions (Altamura and Muckenthaler 2009; Brewer 2007; Chau 2000; Fernandes de Godoy et al. 2007; Gajda et al. 2008; Halliwell 2009; Horwitz et al. 1998; Kazi et al. 2008; Lee et al. 1998; McRae et al. 2009; Rajendran et al. 2007; Ramakrishna et al. 2003; Roijers et al. 2005; Smith et al. 1992; Stadler et al. 2004; Stanley et al. 2006; Stocker and Keaney 2005; Sullivan 2009; Watt et al. 2006; Wolff et al. 2004; Yuan and Li 2008)
Iron depletion by dietary or other means delays the formation of such lesions (Ferrara and Taylor 2005; Halliwell 2009; Lee et al. 1999; Matthews et al. 1997; Ponraj et al. 1999; Ren et al. 2005).
There is a correlation between iron status and atherosclerosis (Ahluwalia et al. 2010; Chau 2000; Day et al. 2003; de Valk and Marx 1999; DePalma et al. 2010; Gozzelino et al. 2010; Howes et al. 2000; Kallianpur 2005; Kartikasari et al. 2009; Kiechl et al. 1997; Lapenna et al. 2007; Marx et al. 2008; McRae et al. 2009; Minqin et al. 2003; Ramakrishna et al. 2003; Ren et al. 2003; Salonen et al. 1992; Shah and Alam 2003; Sullivan 2007, 2009; You et al. 2003; You and Wang 2005; Zacharski et al. 2000; Zacharski and Gerhard 2003) (and zinc is protective only against subsequent calcification, Stadler et al. 2008)
Exogenous ferric iron is deleterious to endothelial function (Rooyakkers et al. 2002)
Iron chelation improves endothelial function (Altamura and Muckenthaler 2009; Duffy et al. 2001; Halliwell 2009; Ishizaka et al. 2005; Saito et al. 2005; Thomas et al. 2006).
Iron levels in plaques correlate with the amount of oxidised proteins therein (Stanley et al. 2006); indeed in one study (Stadler et al. 2004), the EPR-detectable iron (essentially Fe(III)) in atherosclerotic tissue was seventeen times greater than that in the equivalent healthy tissue. I redraw these data in Fig. 7.
It seems clear that the application of similar studies to other diseases in which plaque formation occurs will be of benefit. Indeed, the location of iron in plaques has also been observed, for instance, for Alzheimer’s (e.g. Collingwood et al. 2008; Connor et al. 1992; El Tannir El Tayara et al. 2006; Ghribi et al. 2006; Haacke et al. 2005; Lovell et al. 1998; Morgan et al. 2004; Quintana 2007; Quintana et al. 2006; Sayre et al. 2000b; Schrag et al. 2009), ALS (Leveugle et al. 1997), MS (Haacke et al. 2009) and Parkinson’s (see above).
(snip)(Natural treatments)
Dietary or nutritional/nutraceutical
In addition, many organisms make so-called ‘secondary’ or natural products, whose functions are often unclear but that clearly have evolutionary benefits for the host (Hadacek et al. 2010; Kell et al. 1995). As I also reviewed (Kell 2009a), many iron-chelating natural products exist in (or may be added to, Pócsi et al. 2008) foodstuffs for which no full pharmaceutical regulatory controls are required and which are classed as nutritional substances. Many are polyphenols (ChEBI 26195) (Amic et al. 2007; Arts and Hollman 2005; Auclair et al. 2009; Cemeli et al. 2009; Cheynier 2005; Geronikaki and Gavalas 2006; Halliwell 2007; Jovanovic and Simic 2000; Kandaswami and Middleton 1994; Kiokias et al. 2008; Korkina and Afanas’ev 1997; Linseisen and Rohrmann 2008; Loke et al. 2009; Manach et al. 2004, 2005a, b; Pérez-Jiménez et al. 2010; Perron and Brumaghim 2009; Perron et al. 2008; Petti and Scully 2009; Pietta 2000; Rice-Evans and Packer 2003; Scalbert et al. 2005; Scalbert and Williamson 2000; Seifried et al. 2007; Slemmer et al. 2008; Spencer et al. 2008; Yadav and Bhatnagar 2007a, b, 2010), including the anthocyanins that proved chemoprotective (Butelli et al. 2008) in a mouse p53 cancer model. Since the previous review (Kell 2009a), I would draw particular attention to a comprehensive overview of the subject (Perron and Brumaghim 2009), as well as new reviews and papers on the chief polyphenol in green tea, (−)epigallocatechin-3-gallate (ChEBI 4806) (Adhami et al. 2009; Butt and Sultan 2009; Hsieh et al. 2009; Jimenez-Del-Rio et al. 2010; Johnson et al. 2010; Pandey and Gupta 2009; Paterniti et al. 2009; Ramesh et al. 2009; Reznichenko et al. 2010; Suh et al. 2009; Weinreb et al. 2009a), on curcumin (ChEBI 3962) (a constituent of turmeric) (Aggarwal and Harikumar 2009; Aggarwal and Sung 2009; Anand et al. 2010; Basile et al. 2009; Epstein et al. 2009; Hegde et al. 2009; Iqbal et al. 2009; Jiao et al. 2009; Jurenka 2009; Kalpravidh et al. 2010; Majumdar et al. 2009; Messner et al. 2009; Patil et al. 2009; Ravindran et al. 2009; Rivera-Espinoza and Muriel 2009; Thephinlap et al. 2009; Thomas et al. 2009; Tuntipopipat et al. 2009; Wang et al. 2009a), on eugenol (ChEBI 4917) (Nagababu et al. 2010) (and cf. Allen and Cornforth 2009), on nepetoidin caffeic acid esters (Maioli et al. 2010), on quercetin (ChEBI 16243) (Chobot 2010; Kitagawa et al. 2009; Krukoski et al. 2009; Lorrain et al. 2010; Park et al. 2010; Pavlica and Gebhardt 2010; Smirnova et al. 2009; Terao 2009; Vlachodimitropoulou et al. 2010) and on melatonin (CHEBI 16796) (Borah and Mohanakumar 2009; Korkmaz et al. 2008, 2009; Reiter et al. 2009; Sener et al. 2009; Sharma and Haldar 2009; Signorini et al. 2009). Many of the protective effects observed are likely due to the iron chelating, as well as directly antioxidative (redox) properties of these molecules (e.g. Ferrali et al. 1997a; Hague et al. 2006; Halliwell 2009; Halliwell et al. 2005; Hider et al. 2001; Končić et al. 2010; Lopes et al. 1999; Mandel et al. 2004; Mandel and Youdim 2004; Morel et al. 1994; Nijveldt et al. 2001; Rice-Evans et al. 1997; Rice-Evans and Packer 2003; Weinreb et al. 2007, 2009a; Yoshino and Murakami 1998). Other molecules that are not themselves directly antioxidant, but have iron-binding characteristics, may also be of benefit. This is certainly true of phytic acid (phytate; myo-inositol-1,2,3,4,5,6-hexakis phosphate; CHEBI 17401) (Aljandali et al. 2001; Allen and Cornforth 2009; Brune et al. 1989; Davidsson et al. 1994; Doria et al. 2009; Glahn et al. 2002; Graf and Eaton 1990, 1993; Graf et al. 1987; Grases et al. 2001; Hallberg et al. 1989; Han et al. 1994; Hanson et al. 2006; Hawkins et al. 1993; Kamp et al. 1995a, b, 2002; Kim et al. 2008; Kumar et al. 2010; Minihane and Rimbach 2002; Miyamoto et al. 2000; Panduri et al. 2006; Poser et al. 2004; Rao et al. 1991; Rimbach et al. 2008; Sandberg et al. 1999; Schlemmer et al. 2009; Shamsuddin 1995; Vucenik and Shamsuddin 2006; Xu et al. 2008).
Phlebotomy
In addition, as follows implicitly from Sullivan’s ‘iron hypothesis’ (Sullivan 1981, 2001, 2003, 2004) (and see Kell 2009a), one way to decrease the amount of iron in the body is to remove it by blood-letting or phlebotomy. While phlebotomy is a very traditional nostrum, often assumed or considered to have rather dubious or at best modest scientific support, there is in fact increasing literature implying its benefits in a variety of conditions (e.g. Aigner et al. 2008; Beutler 2007; Broedbaek et al. 2009; Brudevold et al. 2008; Busca et al. 2010; DePalma et al. 2007, 2010; Dereure et al. 2008; Desai et al. 2008; Dwyer et al. 2009; Equitani et al. 2008; Facchini et al. 2002; Fargion et al. 2002; Fernández-Real et al. 2002; Fujita et al. 2009; Fujita and Takei 2007; Hayashi et al. 2006; Hayashi and Yano 2002; Heathcote 2004; Horwitz and Rosenthal 1999; Hua et al. 2001; Kaito 2007; Kaito et al. 2006; Kato et al. 2001, 2007; Kom et al. 2006; Rajpathak et al. 2009; Sullivan 2009; Sumida et al. 2009; Tanaka et al. 2007, 2009; Toyokuni 2009b; Zacharski et al. 2008). Plausibly such benefits are due to its role in decreasing iron stores.
