Antiglycation Studies of Pd(II)-Hydrazide Complexes

Antiglycation Studies of Pd(II)-Hydrazide Complexes Introduction Glycation is a non-enzymatic spontaneous reaction between sugars and coexisting protein followed by a complex cascade of reactions including dehydration, redox reaction and other rearrangements [1, 2] forming advanced glycation end products (AGEs) [3]. Glycation reactions depend on the generation of reactive oxygen species by trace amounts of redox active metal ions [4] and on the degree and duration of hyperglycemia in vivo [5]. Glycation damages the collagen and elastin throughout the body. It is generally accepted that accumulation of tissue AGEs together with enhanced oxidative stress has an important role in the progression of aging and diabetic complications including retinopathy, neuropathy, embryopathy, delayed healing of wounds and others [6-10]. The increase in diabetic complications is the major cause of increased morbidity and mortality rate that has enhanced considerably in the two decades [11]. It has been estimated that the number of cases of DM will reach to 366 milli on by 2030 [12, 13] showing in fact a great challenge to healthcare systems [14]. The failure of existing antidiabetic drugs are forcing researchers to find out new inhibitors of proteins responsible for glycation in order to have a long term and sustainable solution for management of diabetes and age-related diseases. Protein Glycation The protein glycation, also called Millard reaction, involves non-enzymatic coupling of proteins with reducing sugars eventually producing advanced end products. The glycation is a spontaneous reaction, which stimulates the degradation of proteins with modification of their structures and biological activity [1-3]. Various reducing sugars including glucose, lactose, fructose, xylose, deoxyribose and galactose may take part in protein glycation [15]. Chemistry and Mechanism of Protein Glycation The protein glycation process initiates with the reaction of carbonyl (keto or aldehydic) group of reducing sugar with free amino group of protein forming a labile Schiff base 16. This is called early stage of glycation. The Schiff bases are then transformed through Amadori rearrangement into comparatively stable compounds known as Amadori products. At acidic pH or under oxidative conditions, the Amadori products or Schiff bases undergo degradation generating extremely reactive 1, 2-dicarbonyl compounds, such as methylglyoxal (Figure 94) 17-21. The formation of protein dicarbonyls through a protein enediol may generate superoxide radicals in the presence of transition metal ions and molecular oxygen 22. The superoxide radicals can be converted into most reactive hydroxyl radical via Fenton reaction 7. The reactive carbonyl compounds subsequently react with amino groups of neighboring proteins producing protein dicarbonyl compounds, which further contribute in the formation of various types of protein crosslinks and adducts called ‘Advanced Glycation End Products’ (AGEs). The autoxidation of Amadori products to AGEs is described as glycoxidation process. Figure 94. Structures of some reactive dicarbonyl glycation intermediates Advanced Glycation End Products The advanced glycation end products (AGEs) comprise a complex heterogeneous group of compounds produced primarily through the reaction of reactive carbonyls and proteins. AGEs demonstrate to have diverse molecular biological functions and structures 18, 23]. The amino, sulphydryl and guanidinum functional groups occurring in the intracellular and extracellular proteins are the main targets of reactive carbonyl compounds. Various AGEs have been recognized in different tissues that can be categorized into three major groups: fluorescent cross-linked AGEs (e.g. pentosidine and crossline), non-fluorescent cross-linked AGEs (e.g. alkyl formyl glycosyl pyrrole and arginine-lysine imidazole cross-links) and non-cross linked AGEs (e.g. pyrraline and N-(carboxylmethyl) lysine) 18. The structures of some AGEs are presented in Figure 95. Figure 95. Structures of selected advanced glycation end products Factors Affecting the Formation of AGEs In physiological environment, the generation of AGEs is a relatively slow process. Accordingly, the AGEs accumulation is dominant in long-lived structural proteins, for instance, tissue collagens and lens crystallins. The oxidative conditions are known to accelerate the formation of AGEs, which slows down under anaerobic environment [24]. The transition metal ions may induce the auto-oxidation of sugars to produce keto aldehydes and hydrogen peroxide that speed up the formation of AGEs [25]. The amount of AGEs formed is increased as a function of time and concentration of glucose and hence the AGEs formation is enhanced with aging and under diabetic conditions [26]. Site Specificity of Glycation of Proteins Glycation of protein is considered as a specific reaction; however, it is less specific compared to enzymatic glycosylation. Glycation often takes place at specialized site in the protein, such as the substrate binding site (e.g. Arg-39) of RNase, the allosteric site (e.g. ÃŽ ²V1) of hemoglobin, and the drug binding sites (e.g. Arg-410) on albumin [27]. The specificity of glycation may be determined by endogenous ligands and the structure of protein especially an amino acid sequence within the protein. The specificity of protein glycation is usually affected by both basic and acidic neighboring groups [28], either via catalysis of Amadori rearrangement (the rate-limiting step of protein glycation), or via effecting pKa of amino group that contributes in enhancing its nucleophilicity and formation kinetics of Schiff bases. This shows that there is a variation in the respective rate and extent of glycation shown by amino groups in the protein. The anionic ligands also catalyze the pote ntial glycation of proteins at specific sites [27]. Exogenous Sources of AGEs The formation of AGEs via Maillard reaction was originally described for physical and chemical changes occurring during heating of food [29]. Beside the natural formation of AGEs inside the body, there are some exogenous sources of increased AGEs including diet enriched with AGEs and smoking. The extent of absorption of AGEs ingested with food is very small [30]. However, there is a strong relationship of AGEs circulating in the human body with the AGEs ingested [31]. It has been investigated that tobacco smoke increases the formation of AGEs on plasma proteins due to containing some products, which produce protein crosslinks and AGE-like fluorescence and mutagenicity [32]. For example, the diarbonyl compounds, glyoxal and metbylglyoxal, are most likely to be present in cigarette smoke that act as mediators of AGE formation and formed by thermal decomposition of existing saccharides. Accordingly, the serum of diabetic smokers reveals enhanced levels of AGEs relative to diabetic non-smokers [33]. Similarly, the smokers are more susceptible to incidence of cataract, cardiovascular and lungs diseases as compared to non-smokers due to smoke-mediated AGEs formation [34]. Toxicity or Pathological Conditions Associated to Glycation and AGEs Formation The AGEs are more prone to proteolysis and degradation as compared to the original proteins. The accumulation of AGEs has toxic biological effects, causing disruption of many cellular processes leading to various pathologies. The AGEs as well as intermediate glycation products such as reactive carbonyls induce the production of free radicals in vitro and in vivo [35, 36] and hence increased oxidative stress [37]. The glycation-mediated free radicals are the major cause of protein fragmentation as well as oxidation of lipids (lipid peroxidation) and nucleic acids [7]. The reactive dicarbonyls have ability to bind with naturally active proteins of diverse physiology via intra- and inter-molecular cross linking resulting in deactivation of enzymes, transcription factors, membrane transporters and signaling components with eventual protein degradation and cytotoxicity [38-40]. The AGEs also bind to cell membrane receptors inducing signal cascades leading to inappropriate gene expressions and cellular activities [18]. The elevated level of AGEs in tissues has a strong correlation with severity of diabetic complications [41, 42]. This is because of modification of enzymatic activity in multiple ways including binding of ligand, change in protein half life, increased membrane permeability, decreased binding ability of insulin to its receptors, increased atherogenicity of LPL and variation in the immunogenicity [43-45]. The main diabetic complications include impaired wound healing and the serious damage and failure of various vital organs such as kidneys (nephropathy), nerves (neuropathy), eyes (cataract, retinopathy), blood vessels (atherosclerosis) and heart (cardiomyopathy) [11, 34, 46, 47]. The AGEs formation is also associated to aging, Alzheimer’s disease and other chronic disorders [17, 10, 48-50]. Natural Biological Defense Mechanism against Glycation and AGEs The human body presents a certain mechanism to inhibit the glycation of protein and resulting AGEs formation. For example, ÃŽ ±-keto-glutaraldehyde dehydrogenase, a liver enzyme, has a capability to inactive 3-deoxyglucosone (3-DG), Arnadori-derived reactive intermediate and hence prevents the generation of AGEs [41]. The other enzymes such as aldose reductase and glyoxylase system (I and II) can catalyze the deglycation of reactive intermediate methylglyoxal into D-lactase [51]. Amadoriases are the group of enzymes found in Aspergillus, which catalyze the deglycation of Amadori products [52]. Some NADPH-dependant exogenous enzymes such as aldose reductase and oxoaldehyde reductase that metabolize ÃŽ ±-dicarbonyls, have the ability to reduce 3-DG and thus regulate the formation of AGEs [53]. Similarly, different plasma amines may reduce AGEs formation through reaction with carbonyl groups of sugar and Amadori compounds [54]. Antioxidants such as vitamin E and vitamin C, provide prote ction against glycation-mediated free radicals, whereas, ceruloplasmin and other transport proteins bind with transition metal ions such as Cu2+, preventing them to take part in glycoxidation reactions or autoxidative glycation [55]. Inhibition of Protein Glycation and AGEs Several attempts have been made earlier to explore pharmacologically active antiglycating agents to prevent or slow down the production of AGEs [56]. The major side effects associated with antiglycation therapy limit the use and necessitate the discovery of new inhibitors of glycation with reduced toxicity and long half life to be implicated for large time span. Currently, two therapeutic strategies are highly successful having great effectiveness against diabetic complications and normal aging; one is the inhibition of formation of AGEs and other is the breaking of already established AGEs cross-linkages [57]. Promising Inhibitors of Glycation with Their Mechanism of Inhibition The antiglycating agents such as aminoguanidine, rutin, antioxidants, aspirin and other AGEs breakers have been examined extensively and received great interest. The structures of some potential antiglycating agents are depicted in Figure 96. Aminoguanidine Aminoguanidine is a derivative of hydrazine that inhibits the generation of AGEs and glucose-derived collagen cross-links during in vitro studies [58]. Aminoguanidine does not act on already formed AGEs but it reacts with reactive Amadori products such as 3-deoxyglucosone preventing additional rearrangements and intermediates crosslinking [59]. In addition, aminoguanidine is a free radical scavenger that contributes in reducing oxidative stress [60]. The treatment of diabetic animal models with aminoguanidine reduces AGEs accumulation, kidney lesions, albuminuria and long-term diabetic complications including retinopathy, nephropathy and neuropathy [61]. Aminoguanidine also exerts positive effect on the speed of nerve conduction [22]. Aminoguanidine therapy is limited by serious toxic effects attributable to high reactivity, subliminal concentrations and rapid renal clearance. The human trials with aminoguanidine experience vasculitis (inflammation of lymph or blood vessel), liver fu nction abnormalities [62] and less frequent flu-like symptoms, nausea and headache [63]. Figure 96. Structures of some potential antiglycating agents Aspirin Acetylsalicylic acid commonly known as aspirin is an analgesic has well known analgesic drug that also shows the preventive action against formation of cataract under diabetic conditions. Aspirin may limit the sugar-mediated formation of Amadori products by acetylation of free amino residues of proteins. Aspirin also stops the crosslinking of tendon in rat tail in vitro through inhibition of glycoxidation. Furthermore, aspirin is a free radical scavenger [64]. However, the use of aspirin is unlikely in controlling late diabetic complications because of some serious gastrointestinal side effects [41]. Rutin Rutin is a common flavonoid of vegetables and fruits that modulates the AGEs generation in vitro. The flavonoids including rutin that contain vicinal dihydroxyl groups have established their significant role as antiglycating agents. The mechanism of inhibition by rutin is suggested to involve the trapping of amino groups in proteins at early stage of glycation, especially in ketoamine formation, by rutin metabolites like keto-quinone intermediates. Rutin has shown significant inhibitory effect against hemoglobin glycation and it is more efficient compared to aminoguanidine [65]. Antioxidnats Since non-enzymatic glycation of protein is significantly accelerated by excessive generation of free radicals, the antioxidants and other free radical scavengers are expected to inhibit the process of glycation [24]. For example, vitamin E has been reported to appreciably reduce the glycation of hemoglobin [66]. The compounds that exhibit both antioxidant and antiglycation properties e.g. aminosalicylic acid, can protect endothelial cells with better efficacy than aminoguanidine against adverse effects of glycation and high glucose levels in vitro [46]. Similarly, carnosine that is a naural antioxidant and antiglycating agent, inhibits sugar-induced cross-linking of proteins by reaction with methylglyoxal and also sequesters metal ions (e.g. copper and zinc). Carnosine has shown its role in the treatment of cataracts and other diseases [67]. The glycation-derived free radicals generation may be reduced by chelation of transition metal ions, which are responsible for monosaccharide a utoxidation. For instance, the metal chelator, diethylenetriamine penta acetic acid has shown the inhibition of glucose autoxidation [68, 69]. AGE-Breakers AGE-breakers are the compounds, which remove AGEs cross-links through breakdown of ÃŽ ±-dicarbonyl bonds in glucose-derived cross-links of proteins [70]. However, the exact mechanism of inhibition for cross-link breaking is unclear so far. N-phenacylthiazolium bromide (PTB) and its chloride form, alagebrium chloride (ALT-711) are the examples of AGE-breakers. It has been demonstrated that the increased arterial stiffness related to diabetes is successfully reversed through a short treatment with AGE-breaker, ALT-711. The cardiovascular stiffness related to normal aging process can also be reduced by ALT-711. For example, the treatment of normal aged dogs with AGE cross-link breaker has shown noticeable decrease in stiffness of left ventricle chamber [71]. The clinical trial studies on diabetic humans, dogs and other animals indicate the potentially promising use of antiglycation therapy in near future to prevent diabetic complications and other diseases related to protein glycation [56].

June Yip proposes post colonialism to evaluate Taiwanese films Essay

June Yip analyzes Taiwan in the book Envisioning Taiwan as a new breed of country in the postcolonial era which has least interest in the idea of nation-state, maintaining it’s very local faces as well as open to international influences with much surprise. Yip takes a look at Taiwan’s post-national territory status through its fiction and cinema movement concentrating her attention to filmmaker Hou Hsiao-hsien. (Winterton) Taiwan has a long history of colonialism and suppression, but the multinational capitalism, mass migration, the arrival of new electronic media; all these encouraged a postmodern culture and have questioned the traditional limit as well as made the notion of nation irrelevant. June Yip emphasizes the hybrid nature of identity as fallout of postmodernism, is vastly reflected in the present form of Taiwanese films. The earlier versions were more conventional and guarded the theme of nationhood. She points in her book Hou’s films present a picture â€Å"the island as an increasingly complex and hybrid social space, an ever-changing formation†. (Yip, 230) Yip focuses that Taiwanese New Cinema, emerged in the 1980’s and its patrons are fascinated with displaying the socio-historical qualities of modern Taiwan’s experience and also to form a sense of Taiwanese cultural identity with centralizing on the search for nationhood in their works. They represent the tough transition period of Taiwan’s history through which the island came to the global order and try to depict the same in their films with â€Å"a quest for an understanding of a modern Taiwanese experience† and rising questions from present and future. (Yip, 10) Yip also presents the grim picture of Taiwan’s history where under various regimes; either Japanese or Chinese, the linguistic medium of films was strictly regulated by the ruling authorities. Most of these languages were foreign to the locals while the local medium was eclipsed. So, in modern Taiwanese cinema, a global touch could be felt where characters easily switch from Taiwanese to Mandarin to Japanese to English, showcasing a multicultural effect. (Yip, 6) Yip clarifies that Taiwan’s cultural awareness took time to surface itself on cinema due to its colonial Hanover. As there is a strong link between cinema and the idea of nationhood but in the later half of the 20th century the cinema carried a huge responsibility of nation building as being a visual medium. Government was always involved in making of Taiwanese films but in 1990’s it felt the need to loose the belts as to get back commercial as well as critical acclaim. Most of the film personalities have grown the age of rigidity, so when they started working they tries their best to free themselves from the knuckles and criticized the government under its banner itself as well as displayed the new experiences with global changes. The films Three Times and Puppetmaster have shown the changes of post colonialism. Three Times is a film consisting of three episodes based in three periods of Taiwanese history showcasing the problems of the turbulent times in the history, urge for freedom and also the confusion prevailing in a contemporary city. The Puppet master recollects the life of a puppeteer spanning during the period of Japanese occupation of the island and portraying the sorry state of the Taiwanese people and their hardships and also depicts the loss of tradition under suppression and western influence. Both the films in their respective themes lament sufferings of the history and urge to come out of the rigid circumstances supporting Yip’s thesis. (Schumann) While The Wedding Banquet is a drama with humorous touch where personal relationships, based on generation and cultural conflicts within individuals of slender theme rather matching the concept of analysis of Yip of Taiwanese cinema.

Industrialization in England Essay - 1828 Words

The world has changed in many ways throughout history. Industrialization has changed England in many ways. The Industrial Revolution was too hard on the men, women, and children in England. The changes that occurred in the economy and society in Britain during the late 18th and 19th century is known as the Industrial Revolution (McCloskey Int.). The Industrial Revolution was a drawn-out process that transformed Britain’s economy from the production of goods by hand to the production of goods by machine (Thackerary 1). During this time the number of people employed in industrial manufacturing, making many different goods, and especially making textiles, iron goods, metal waves, and pottery increased dramatically (McCloskey Int.). At the†¦show more content†¦In 1851, the employment of textiles rose from 1.3 million to over 1.5 million by 1911. Clothing went from nine hundred thousand to over 1.2 million workers. Engineering and metal working rose from over half a millio n workers to nearly two million. In the paper and printing industry the employment increased five-fold to nearly four hundred thousand employees. Employment in the chemical, oil, and soap industries increased over four-fold to two hundred thousand workers (Mingay 27). By 1849, there were twelve steel-pen factories employing an average of one hundred fifty-four employees in each factory. Mechanized industries employed less than two million workers in 1851 (Mingay 26). In 1871 there were one hundred forty-five factories making boots and shoes, and each factory employed an average of one hundred twenty-five workers. There were fifty-eight cheap clothing factories that employed an average of one hundred thirty-six workers a piece. The expansion of the market at home and overseas was the ultimate reason for the growth of the factories in Britain (Mingay 26). 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Children have been used in armed conflicts since time...

Children have been used in armed conflicts since time immemorial. Today the world sees this issue as immoral and reprehensible. However, the use of children in armed conflicts continues. Statistics produced by various organizations including the United Nations human rights, Human Rights Watch and Peace Direct suggests that anywhere from 200,000 to 300,000 children under the age of 18 are serving as child soldiers in 50 different conflicts across 33 different countries. These young people are often kidnapped or forced into these positions. They are forced into accepting being child soldiers through poverty and the promise of assistance to their families and to themselves. They are also forced into this situation by being witnesses to†¦show more content†¦While this indicates an active interest on the part of world leaders to protect children, it has not been effective in eradicating the problem. In Mexico, all young men of the age of 18 or older must serve in the military for one year, although service is predicated by a lottery system, which determines whether they are to be on stand-by, serve actively, or must do community service. However, with consent, individuals may sign up at the age of 16. According to reports, there are no child soldiers serving in the armed forces of Mexico. Where child soldiers are found in Mexico are with the opposition forces in the Chiapas region and with the paramilitary forces maintained by the drug cartels. It has been noted that children, especially boys, get recruited by the cartels as young as 11. These children live primarily in the poorest regions of Mexico. Their families depend on the income these children generate for their survival. In these areas, the drug cartels behave in a similar fashion as the warlords of Afghanistan. For the people of these areas, the drug lords are seen as benign and helpful. This situation will continue un til the drug cartels and all drug trafficking they handle is