Antiglycation and Antioxidant Effect of Carnosine against Glucose Degradation Products in Peritoneal Mesothelial Cells

Alhamdani, Mohamed-Saiel Saeed; Al-Kassir, Abdul-Hameed A.-M.; Abbas, Fawzi K.H.; Jaleel, Nidham A.; Altaee, Maha Fakhry

doi:10.1159/000106509

Cited by 40 publications

(30 citation statements)

References 65 publications

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“…Cheng et al (2011) demonstrated in cultured neurons that MDA caused protein cross-linking and cytotoxicity, and that both these effects were reversed by carnosine treatment. Carnosine was found to enhance HPMC (human peritoneal mesothelial cells) viability against the toxic effect of RCS originated from glucose oxidation through the protection of cellular protein from modification and from ROS-mediated oxidative damage (Alhamdani et al 2007b). Regarding the in vivo evidence of carnosine to inhibit AGEs and ALEs formation, we recently found that carnosine treatment of Zucker rats for 24 weeks significantly reduced the urinary AGEs, protein carbonylation in the kidney and improved collagen solubility as an indicator of the extent of collagen crosslinking .…”

Section: Carnosine Prevents Ales and Ages Formationmentioning

confidence: 99%

Transforming dietary peptides in promising lead compounds: the case of bioavailable carnosine analogs

Vistoli

Carini

2012

Amino Acids

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The ability of carnosine to prevent advanced glycoxidation end products (AGEs) and advanced lipoxidation end products (ALEs) formation, on the one hand, and the convincing evidence that these compounds act as pathogenetic factors, on the other hand, strongly support carnosine as a promising therapeutic agent for oxidative-based diseases. The mechanism/s by which carnosine inhibits AGEs and ALEs is still under investigation but an emerging hypothesis is that carnosine acts by deactivating the AGEs and ALEs precursors and in particular the reactive carbonyl species (RCS) generated by both lipid and sugar oxidation. The ability of carnosine to inhibit AGEs and ALEs formation and the corresponding biological effects has been demonstrated in several in vitro studies and in some animal models. However, such effects are in line of principle, limited in humans, due to the effect of serum carnosinase (absent in rodents), which catalyzes the carnosine hydrolysis to its constitutive amino acids. Such a limitation has prompted a great interest in the design of carnosine derivatives, which maintaining (or improving) the reactivity with RCS, are more resistant to carnosinase. The present paper intends to critically review the most recent studies oriented to obtaining carnosine derivatives, optimized in terms of reactivity with RCS, selectivity (no reaction with physiological aldehydes) and the pharmacokinetic profile (mainly through an enhanced resistance to carnosinase hydrolysis). The review also includes a brief description of AGEs and ALEs as drug targets and the evidence so far reported regarding the ability of carnosine as inhibitor of AGEs and ALEs formation and the proposed reaction mechanisms.

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Section: Carnosine Prevents Ales and Ages Formationmentioning

confidence: 99%

Transforming dietary peptides in promising lead compounds: the case of bioavailable carnosine analogs

Vistoli

Carini

2012

Amino Acids

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“…There is much evidence, mostly obtained from model systems, suggesting that carnosine can suppress protein modification mediated by reactive oxygen species (ROS) (Kohen et al, 1988;Boldyrev 2005;Alhamdani et al, 2007aAlhamdani et al, & 2007b, reactive nitrogen species (RNS) (Calabrese et al, 2005;Fontana et al, 2002), glycating agents (Hipkiss et al, 1995;Vinson and Howard, 1996;Seidler, 2000) and deleterious aldehydes such as malondialdehyde (Hipkiss et al 1997(Hipkiss et al and 1998a(Hipkiss et al and 1998b, hydroxynonenal (Aldini et al, 2002 and, acrolein Carini et al, 2003) and methylglyoxal (MG) (Hipkiss and Chana, 1998). Carnosine also inhibited the cross-linking of MG-modified protein with normal polypeptides (Hipkiss and Chana, 1998), most likely by forming adducts with the MG-induced protein carbonyl groups (Brownson and Hipkiss, 2000).…”

Section: Carnosine and Post-synthetic Protein Modificationmentioning

confidence: 99%

On the enigma of carnosine’s anti-ageing actions

Hipkiss¹

2009

Experimental Gerontology

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Carnosine ( -alanyl-L-histidine) has described as a forgotten and enigmatic dipeptide. Carnosine's enigma is particularly exemplified by its apparent anti-ageing actions; it suppresses cultured human fibroblast senescence and delays ageing in senescence-accelerated mice and Drosophila, but the mechanisms reponsible remain uncertain. In addition to carnosine's well-documented anti-oxidant, anti-glycating, aldehyde-scavenging and toxic metal-ion chelating properties, its ability to influence the metabolism of altered polypeptides, whose accumulation characterises the senescent phenotype, should also be considered. When added to cultured cells, carnosine was found in a recent study to suppress phosphorylation of the translational initiation factor eIF4E resulting in decreased translation frequency of certain mRNA species. Mutations in the gene coding for eIF4E in nemtodes extend organism lifespan, hence carnosine's anti-ageing effects may be a consequence of decreased error-protein synthesis which in turn lowers formation of protein carbonyls and increases protease availability for degradation of polypeptides altered postsynthetically. Other studies have revealed carnosine-induced upregulation of stress protein expression and nitric oxide synthesis, both of which may stimulate proteasomal elimination of altered proteins. Some anti-convulsants can enhance nematode longevity and suppress the effects of a protein repair defect in mice, and as carnosine exerts anti-convulsant effects in rodents, it is speculated that the dipeptide may participate in the repair of protein isoaspartyl groups. These new observations only add to the enigma of carnosine's real in vivo functions. More experimentation is clearly required. ACCEPTED MANUSCRIPT 3 Carnosine and ageing.The naturally-occurring dipeptide carnosine ( -alanyl-L-histidine) has been described as forgotten and enigmatic (Bauer, 2005): the present paper is an attempt to rectify the former opinion, but, however only adds to the latter view. Amongst carnosine's enigmatic properties are its apparent anti-ageing actions; the dipeptide is one of a very few naturally-occurring compounds which suppresses cell senescence, induces rejuvenating effects Holliday, 1994 and, and protects against telomere shortening (Shao et al., 2004) in cultured human fibroblasts. The dipeptide also extends the life-span of senescence-accelerated mice (Yuneva et al., 1999) and Drosophila (Yuneva et al., 2002). There are many possible mechanisms by which carnosine exerts these anti-ageing actions however, some of which were summarized a decade ago (Hipkiss, 1998). Meanwhile there have been a number of publications suggesting further possible routes by which carnosine could suppress

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“…Of note, in a carnosine or beta-alanine supplementation study in rats with diet-induced obesity, it was recently demonstrated that plasma rather than muscle carnosine is involved in ameliorating high-fat diet-induced lipoxidative and inflammatory stress (Stegen et al 2015). Carnosine supplementation studies in murine models demonstrated therapeutic efficacy of carnosine to ameliorate diabetes and DN, as albuminuria and histological lesions were reduced after supplementation (Lee et al 2005;Alhamdani et al 2007;Sauerhöfer et al 2007;Riedl et al 2011;Aldini et al 2011;Nagai et al 2012;Peters et al 2012;Albrecht et al 2017).…”

Section: Introductionmentioning

confidence: 99%

Identification and characterisation of carnostatine (SAN9812), a potent and selective carnosinase (CN1) inhibitor with in vivo activity

et al. 2018

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Carnosinase 1 (CN1) has been postulated to be a susceptibility factor for developing diabetic nephropathy (DN). Although its major substrate, carnosine, is beneficial in rodent models of DN, translation of these findings to humans has been hampered by high CN1 activity in human serum resulting in rapid degradation of carnosine. To overcome this hurdle, we screened a protease-directed small-molecule library for inhibitors of human recombinant CN1. We identified SAN9812 as a potent and highly selective inhibitor of CN1 activity with a K i of 11 nM. It also inhibited CN1 activity in human serum and serum of transgenic mice-overexpressing human CN1. Subcutaneous administration of 30 mg/kg SAN9812 led to a sustained reduction in circulating CN1 activity in human CN1 transgenic (TG) mice. Simultaneous administration of carnosine and SAN9812 increased carnosine levels in plasma and kidney by up to 100-fold compared to treatment-naïve CN1-overexpressing mice. To our knowledge, this is the first study reporting on a potent and selective CN1 inhibitor with in vivo activity. SAN9812, also called carnostatine, may be used to increase renal carnosine concentration as a potential therapeutic modality for renal diseases linked to glycoxidative conditions.

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Antiglycation and Antioxidant Effect of Carnosine against Glucose Degradation Products in Peritoneal Mesothelial Cells

Cited by 40 publications

References 65 publications

Transforming dietary peptides in promising lead compounds: the case of bioavailable carnosine analogs

Transforming dietary peptides in promising lead compounds: the case of bioavailable carnosine analogs

On the enigma of carnosine’s anti-ageing actions

Identification and characterisation of carnostatine (SAN9812), a potent and selective carnosinase (CN1) inhibitor with in vivo activity

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