Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
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We wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
IntechOpen is proud to announce that 191 of our authors have made the Clarivate™ Highly Cited Researchers List for 2020, ranking them among the top 1% most-cited.
\n\n
Throughout the years, the list has named a total of 261 IntechOpen authors as Highly Cited. Of those researchers, 69 have been featured on the list multiple times.
\n\n\n\n
Released this past November, the list is based on data collected from the Web of Science and highlights some of the world’s most influential scientific minds by naming the researchers whose publications over the previous decade have included a high number of Highly Cited Papers placing them among the top 1% most-cited.
\n\n
We wish to congratulate all of the researchers named and especially our authors on this amazing accomplishment! We are happy and proud to share in their success!
Note: Edited in March 2021
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From their direct and recent experience, the readers can achieve a wide vision on the new and ongoing potentialities of different synthetic and engineered biomaterials. Contributions were selected not based on a direct market or clinical interest, but based on results coming from very fundamental studies. This too will allow to gain a more general view of what and how the various biomaterials can do and work for, along with the methodologies necessary to design, develop and characterize them, without the restrictions necessarily imposed by industrial or profit concerns. The chapters have been arranged to give readers an organized view of this research area. In particular, this book contains 25 chapters related to recent researches on new and known materials, with a particular attention to their physical, mechanical and chemical characterization, along with biocompatibility and hystopathological studies. 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1. Introduction
This chapter begins with general information on the role of 5’-AMP activated kinase (AMPK) in human physiology and the molecular mechanisms that control this kinase. We discuss the functions of AMPK in different tissues and their relationship to type 2 diabetes. AMPK substrates in different subcellular organelles and compartments are described, and we speculate how the localized action of AMPK could help to control type 2 diabetes. Our review concludes with future directions that are based on the compartment-specific action of AMPK to develop new therapeutic strategies for patients with type 2 diabetes.
1.1. AMPK activity is critical to cell physiology in different tissues and organs
Owing to its pivotal role in the control of glucose homeostasis, carbohydrate, lipid and protein metabolism AMPK is a key player in many human diseases and disorders (Fogarty & Hardie, 2010; Lage et al., 2008; Towler & Hardie, 2007; Viollet et al., 2009b). In particular, the low activation state of AMPK could contribute to the increase in type 2 diabetes and obesity (Hardie et al., 2006). Moreover, as essential regulator of glucose homeostasis and lipid metabolism, AMPK has become an important therapeutic target in type 2 diabetes and obesity. This is exemplified by metformin and thiazolidinedione derivatives (TZDs); these drugs are used for therapeutic intervention in type 2 diabetes and lead to the activation of AMPK.
Figure 1.
The role of AMPK in different organs and tissues. AMPK controls the physiology of multiple organs which are critical to type 2 diabetes, obesity and other metabolic diseases. As such, AMPK regulates both anabolic and catabolic pathways as well as the function and biogenesis of organelles. See text for details.
2. Organization and activation of AMPK
AMPK senses a drop in cellular energy as it is induced by a reduction in glucose availability or other metabolic stresses. The overall consequence of AMPK activation is a change in metabolism; thus, when the AMP/ATP ratio increases AMPK becomes activated in order to rescue the energy balance. As a result of AMPK activation, the cellular metabolism switches from anabolic to catabolic processes. This metabolic shift is accomplished by the AMPK-dependent phosphorylation of multiple targets which are located in different cellular organelles and compartments (see below).
The heterotrimeric enzyme AMPK (Fig. 2; αβγ) contains one catalytic α subunit that is encoded by two genes (α1 and α2). The regulatory β and γ subunits are encoded by two and three genes, respectively (Hardie et al., 2006). The two β subunits (β1, β2) can be myristoylated and phosphorylated, and these modifications may impact the activation and intracellular localization of AMPK (Oakhill et al., 2010; Warden et al., 2001; see below). The γ subunits (γ1, γ2, γ3) bind AMP and ATP in a mutually exclusive fashion, this AMP binding is important to the activation of the enzyme. The subunit composition of AMPK heterotrimers varies in different tissues and can affect the activation of the kinase (Canto & Auwerx, 2010; Cheung et al., 2000; Steinberg & Kemp, 2009; Viollet et al., 2010).
2.1. Control of AMPK activity by phosphorylation and changes in AMPK concentration
The importance of AMPK as a key regulator in cellular metabolism requires a tight control of the enzyme. The rapid regulation of AMPK activity is based on at least three mechanisms that contribute to AMPK activation (Oakhill et al., 2010; Sanders et al., 2007; Shackelford & Shaw, 2009; Steinberg & Kemp, 2009). (a) The most important step for AMPK activation is the phosphorylation of Thr172 of the α subunit which can be modified by the upstream kinases LKB1, CaMKKβ and TAK1 (Fig. 2). Thr172 is phosphorylated when the energy state of the cell is low, i.e. when the AMP/ATP ratio rises. Under these conditions, AMP binding to the regulatory γ subunit promotes the subsequent Thr172 phosphorylation. LKB1 is the major upstream kinase for this event in tissues like skeletal muscle. The effect of AMP binding depends on the type of γ subunit (Cheung et al., 2000). Specifically, AMP-binding to γ2 subunits leads to the largest increase in AMPK activity. By contrast, a relative small change is observed for the γ3 subunit which is mostly synthesized in glycolytic skeletal muscle. Recent data suggest that the β subunits also play a crucial role in AMPK activation. It was proposed that β subunit myristoylation provides a switch that is a prerequisite for Thr172 phosphorylation (Oakhill et al., 2010). (b) Aside from changes in the AMP/ATP ratio, a rise in intracellular Ca2+ concentrations triggers Thr172 phosphorylation. This modification is mediated by CaMKKβ and particularly important in tissues where LKB1 is not the predominant kinase for Thr172. At present, the role of TAK1 in AMPK activation is not fully understood. (c) AMPK activation can be prolonged by preventing the dephosphorylation of Thr172, a process catalyzed by phosphatases PP2A and PP2C (Kim et al., 2009a; Nagata & Hirata, 2010).
Figure 2.
Organization of AMPK and regulation of kinase activity by phosphorylation.AMPK is a heterotrimeric enzyme that is activated by phosphorylation on Thr172 of the α subunit. Several upstream kinases can modify Thr172; they include LKB, CaMKKβ and TAK1. The activity of AMPK can be reduced by different mechanisms. For example, PP2A and PP2C mediate the dephosphorylation of phospho-Thr172. In addition, PKC and Akt phosphorylate Ser485/491 of the α chain which decreases AMPK activity. Furthermore, PKA-dependent modification of Ser173 diminishes AMPK activity.
Aside from the dephosphorylation of phospho-Thr172, a negative regulation of AMPK involves the phosphorylation of Ser485/491 by PKC and possibly Akt, whereas the decline in activity by Ser173 phosphorylation was ascribed to PKA (Djouder et al., 2010). Such modification on Ser173 may help to fine tune lipid metabolism in adipose tissue.
The tissue-specific regulation of AMPK activity is likely achieved by the combined effects of upstream activating kinases, inactivating phosphatases as well as the synthesis and degradation of AMPK subunits. For example, LKB1 is particularly important to activate AMPK in skeletal muscle, whereas CaMKKβ is crucial in the brain (Ronnett et al., 2009). On the other hand, TNFα alters AMPK activation by modulating the synthesis of PP2C (Lu et al., 2010; Steinberg et al., 2006). Aside from the rapid control of AMPK activation by phosphorylation, changes in the expression of subunit genes or the turnover of AMPK subunits can help to fine tune AMPK activity in some tissues (Barry et al., 2010; Fukuyama et al., 2007; Hallows et al., 2006; Qi et al., 2008; Niesler et al., 2007; Steinberg et al., 2003).
2.2. Pharmacological compounds and other factors that alter AMPK activity
Previous work established the essential role of AMPK in the regulation of carbohydrate, protein and lipid metabolism; this made AMPK a key target for the treatment of type 2 diabetes, obesity and metabolic syndrome (Gruzman, Babai & Sasson, 2009; Hardie, 2008b; Steinberg & Kemp, 2009; Viollet et al., 2010; Viollet et al., 2009b). Indeed, in a clinical setting AMPK activity is altered with the anti-diabetic drug metformin and other biguanides. The drug-induced activation of AMPK has important consequences for the patient; among these is the improvement of insulin resistance.
Pharmacological drugs have also been critical to define how AMPK mediates metabolic control (see Table 1). These compounds employ a variety of molecular mechanisms that culminate in AMPK activation (Gruzman et al., 2009; Hawley et al., 2010; Mantovani & Roy, 2011). For example, the kinase can be activated by a rise in the AMP/ATP ratio, generation of an AMP mimetic or increase in intracellular Ca2+ concentrations (Hawley et al., 2010). Metformin impacts several biological processes that ultimately activate AMPK. These include changes in the respiratory chain, increased synthesis of the protein deacetylase SIRT1 (which activates LKB1) and activation of TAK1 (Caton et al., 2010; Hawley et al., 2002; Hawley et al., 2010; Xie et al., 2006). Phenphormin promotes the LKB1-dependent activation of AMPK by inhibiting mitochondrial complex I (Hawley et al., 2010). Resveratrol prevents the acetylation and concomitant inactivation of the upstream kinase LKB1, this compound also inhibits mitochondrial ATP synthase and may increase the concentration of adiponectin (Hawley et al., 2010; Wang et al., 2011). AICAR generates the AMP mimetic 5-amino-4-imidazolecarboxamide ribotide (ZMP) and causes a drop in cellular ATP and ADP, which leads to AMPK activation (Hawley et al., 2010). Aside from drugs that activate AMPK, compound C serves as an ATP-competitive inhibitor of AMPK that has been used widely. All of the compounds discussed here are established pharmacological tools that alter AMPK activation or enzymatic activity; they have been useful for the analysis of AMPK in vitro, in growing cells and in whole animals. The following table summarizes how AMPK activity can be affected in vitro, growing cells, organs or whole organisms.
Generation of ZMP, which functions as an analog of AMP; activation
Metformin (Biguanide)
Reduces mitochondrial ATP production; activation
Phenformin
Inhibition of respiratory chain, activation
Resveratrol
Change in ATP synthase activity; prevents acetylation of LKB1 via modulation of SIRT1; upregulation of adiponectin synthesis and multimerization; activation
(B) Hormones, cytokines, physiological processes and environmental stressors
Insulin
Inhibition of AMPK activation; mediated by Akt kinase
Ghrelin
Tissue-specific effects; activation in heart and hypothalamus; reduced activity in liver and adipose tissue
Adiponectin
Activation by increase in AMP concentration
Resistin
Tissue-specific effects; reduction of AMPK activity in skeletal muscle
Leptin
Tissue-specific effects; activates α2 heterotrimers; activation in muscle and fat tissue; reduces activity in hypothalamus
TNFα
Acute and chronic effects; acute: activation; chronic: reduction in activity; increase in PP2C
IL-6
Increase in AMP/ATP ratio; activation (note that IL-6 can have different effects on insulin sensitivity)
CNTF (Ciliary neurotrophic factor)
Tissue-specific effects; activation in muscle; activity reduced in hypothalamus
UCP1, UCP3
Uncoupling proteins in mitochondria, change in energy status; activation
Reduction in glucose availability
Change in energy status; activation
Rise in Ca2+ concentration, osmotic stress
CaMKKβ activation
Exercise
Skeletal muscle contraction; activation
Heat shock, oxidative stress
Environmental stressors; transient activation
Ischemia/hypoxia, reactive oxygen species
Metabolism/oxidative stress; activation
Table 1.
Modulators of AMPK activity.The data in Table 1 are compiled from several publications that describe the molecular mechanisms and tissue-specific effects on AMPK activity in detail (Caton et al., 2010; Dzamko & Steinberg, 2009; Hawley et al., 2010; Maeda et al., 2001; Nagata & Hirata, 2010; Steinberg et al., 2009; Viollet et al., 2010). It should be noted that although in most cases a correlation between treatment and changes in AMPK activity has been demonstrated, the molecular mechanisms are not always fully understood. For example, hormone or cytokine-dependent changes in AMP/ATP ratios may be secondary to other signaling events, such as changes in cAMP concentrations. For some of the treatments, it has yet to be established whether AMPK is essential for the downstream physiological effect. More recent experiments with knockout cells and animal models will help to fill these gaps (Viollet et al., 2009a).
3. AMPK functions in different tissues and organs
Although AMPK is present in different tissues and organs, the subunit composition varies, and changes in cell physiology can also alter the profile of expressed subunits (Mahlapuu et al., 2004; Pulinilkunnil et al., 2011; Putman et al., 2007; Quentin et al., 2011; Stapleton et al., 1996; Turnley et al., 1999). Of particular importance at the cellular, organ and organismal level is the ability of AMPK to switch from anabolic to catabolic processes when energy supplies are low. AMPK regulates metabolism and other aspects of cell physiology both under normal and disease conditions; studies with different cells or tissues emphasize the significance of AMPK for cellular metabolism and the response to various forms of stress. Thus, AMPK controls several metabolic pathways that are directly relevant to diabetes and other metabolic diseases or syndromes (Steinberg & Kemp, 2009; Viollet et al., 2010; Zhang et al., 2009). However, AMPK not only provides a sensor for nutrient availability, the kinase is also activated by hormonal signals in peripheral tissues and the hypothalamus (Jorda et al., 2010; Ronnett et al., 2009). Notably, this signaling in the central nervous system contributes to the regulation of food uptake. Research with hepatic, skeletal muscle, adipose, pancreatic and kidney cells is particularly important to our understanding of type 2 diabetes as these cell types are crucial to the etiology or pathophysiology of the disease (Fig. 1). In general, the consequences of AMPK activation can be divided into acute and long-term effects (Mantovani & Roy, 2011; Viollet et al., 2010). Whereas the phosphorylation of key enzymes produces a fast downregulation of ATP-consuming metabolic pathways, long-term effects involve changes in the expression of target genes that control metabolism. Since several recently published excellent reviews covered these topics extensively, Table 2 only summarizes the impact of AMPK activation on tissues that are critical to type 2 diabetes.
Tissue or cell type
Physiological process
Enzyme or process affected by AMPK
Liver
activation of fatty acid oxidation, inhibition of lipogenesis
inhibition of acetyl-CoA carboxylase ACC (Acc1, Acc2)
reduced cholesterol synthesis
HMG-CoA reductase
stimulation of fatty acid uptake
CD36 (a fatty acid translocase) moves to the plasma membrane
changes in lipogenesis and glycolysis due to reduced concentration of transcriptional regulators SREBP1 (sterol response element binding protein-1) and ChREBP (carbohydrate response-element binding protein)
inhibits ChREBP by phosphorylation, reduces the transcription of genes encoding SREBP1 and ChREBP
increase in mitochondrial biogenesis
increased expression of PGC1α and other genes required for mitochondrial biogenesis
glycogen synthesis reduced
inhibition of glycogen synthase
inhibition of gluconeogenesis and hepatic glucose production
changes in the activity, concentration or localization of key enzymes or transcriptional regulators; (phosphoenol pyruvate carboxy kinase, HNF4; TORC2, p300)
Skeletal muscle
stimulation of glucose uptake; fusion of GLUT4 (glucose transporter) containing vesicles with plasma membrane
phosphorylation of AS160 may promote trafficking of vesicles; increased transcription of GLUT4 gene by phosphorylation of HDAC5
increase in mitochondrial biogenesis
increased expression of PGC1α and other genes required for mitochondrial biogenesis
increased fatty acid uptake and oxidation
inhibition of ACC
reduction in protein synthesis
inhibition of mTOR pathway via modification of mTOR, TSC2 and eEF2 kinase
control of glycogen metabolism
inactivation of glycogen synthase
Adipose tissue
increase in fatty acid oxidation
inactivation of ACC
inhibition of lipolysis
phosphorylation of HSL, reduced association of HSL with lipid droplets
Pancreas
inhibition of glucose-induced insulin secretion in β cells
reduced trafficking of vesicles containing insulin
inhibition of transcription of the preproinsulin gene in β cells; stimulation of glucagon secretion in α cells
molecular mechanisms not fully understood
Heart
stimulation of glucose uptake by translocation of GLUT4 to the plasma membrane
fusion of GLUT4 containing vesicles with the plasma membrane
stimulation of glycolysis
activation of 6-phosphofructo-2-kinase → enhances production of fructose 2,6-bisphosphate → stimulates 6-phosphofructo-1-kinase
increase in fatty acid oxidation
inactivation of ACC
control of glycogen metabolism
contributions of AMPK activity not completely understood at the molecular level
Kidney
ameliorates changes linked to diabetic nephropathy
inhibition of mTOR, inhibition of CFTR and other ion channels
Brain
food intake; multiple pathways affected in the hypothalamus; adiponectin, leptin, insulin and ghrelin control AMPK
4. AMPK modulates targets in different subcellular organelles and compartments
4.1. Subcellular distribution of AMPK substrates
The combination and integration of different subcellular events regulated by AMPK enables cells, tissues and organs to coordinate different metabolic pathways in order to achieve and maintain the proper energy balance of the whole organism. Fig. 3 depicts established AMPK substrates according to their presence in different subcellular compartments. Table 3 expands this information and specifies how the AMPK-dependent phosphorylation of individual substrates alters their functions.
It is obvious from Fig. 3 that AMPK phosphorylates a large number of proteins that are associated with distinct organelles or subcellular compartments. Cytoplasmic and mitochondrial substrates of the kinase include enzymes that are involved in fat, protein, glucose and glycogen metabolism. Kinase targets in the plasma membrane consist of ion channels, carriers and receptors, whereas other substrates are linked to the function or trafficking of intracellular membranes. This includes the transport of vesicles containing the glucose transporter GLUT4, because GLUT4 translocation to the plasma membrane is a pre-requisite for efficient glucose uptake in skeletal muscle and other tissues. AS160 and TBC1D1 likely play a role in these processes (Table 3). In the nucleus, the AMPK-mediated modification of transcription factors, transcriptional regulators and a subunit of RNA-polymerase I control the expression of genes that are implicated in specific anabolic and catabolic reactions. The phosphorylation of several of these targets is also critical to the biogenesis of mitochondria and the assembly of ribosomes.
Figure 3.
AMPK affects functions in various cellular compartments and organelles. Examples are shown for the proteins that AMPK modifies in distinct sub-cellular locations. Some of the substrates are present in multiple compartments. PM, plasma membrane. See text and Table 3 for details.
Given the diverse types of AMPK substrates and their presence in different cellular locations, it is helpful to recapitulate their functions (Table 3a). This knowledge is a prerequisite to understand how the dynamic association and action of AMPK in different compartments will impact downstream events.
Substrates that have been established for AMPK heterotrimers that contain the α1 or α2 subunit are shown. For different AMPK substrates the function, effect of AMPK-dependent phosphorylation and the major subcellular localization are depicted. For some substrates, there are cell-type specific differences, and the effect of AMPK-dependent phosphorylation may not be fully understood or controversial. The list of AMPK substrates was compiled from PhosphoSitePlus (phosphosite.org).
Substrates for AMPKα1
Function
Effect of phos-phorylation
Primary intracellular localization
Refe-rences
Acc1; Subunit of acetyl-CoA carboxylase, ACC
Carboxylates acetyl-CoA, thereby generating malonyl-CoA; this step is rate-limiting for FA biosynthesis.
inhibition
cytoplasm
Sun et al., 2006
Acc2; Subunit of acetyl-CoA carboxylase, ACC
Carboxylates acetyl-CoA, thereby generating malonyl-CoA; this step is rate-limiting for FA biosynthesis.
GTPase activating protein for Rab; implicated in GLUT4 exocytosis in skeletal muscle
not fully understood; may regulate glucose uptake
cytoplasm
Eguez et al., 2005; Treebak et al., 2010
HAS2
Hyaluronic acid synthase 2; EC 2.4.1.212; integral membrane protein
inhibition of enzymatic activity
plasma membrane
Vigetti et al., 2011
HDAC5
See above description of AMPKα1 targets
nucleus
p53
See above description of AMPKα1 targets
nucleus
PGC1α
PPAR γ coactivator-1; transcriptional co-activator; association with PPARγ; binds to CREB and nuclear respiratory factors; controls mitochondrial biogenesis
phosphorylation alters activity as transcriptional regulator
nucleus
Jager et al., 2007
PLD1
Phospholipase D1 phophatidylcholine specific; EC 3.1.4.4; linked to Ras signaling; involved in membrane trafficking
activation of enzymatic activity
Golgi, ER
Kim et al., 2010
Table 3a.
Substrates of AMPK heterotrimers containing the α1 or α2 subunit
4.2. Subcellular distribution and trafficking of AMPK
AMPK is associated with different organelles and subcellular compartments; however, little is known about the dynamic nature of this distribution. Analyses of other signaling pathways have demonstrated that the subcellular localization of kinases is critical for the proper response to extra- and intracellular stimuli, and it is likely that the same scenario applies to AMPK. We will therefore briefly review what is currently known about the subcellular localization and trafficking of AMPK.
AMPK is found in the nucleus and cytoplasm which reflects functions for the enzyme in both locations (Kodiha et al., 2007; Witczak et al., 2008). Although the kinase is associated with multiple compartments, α1 and α2 subunits differ in their nucleocytoplasmic distribution. Under normal growth conditions, α1 is predominantly in the cytoplasm, whereas α2 locates to both the nucleus and cytoplasm (Salt et al., 1998). It was further shown that the nuclear localization sequence (NLS) present in the α2 subunit is required for AMPK nuclear translocation (Suzuki et al., 2007), suggesting that the catalytic α subunit is essential for the proper intracellular localization of the holoenzyme. Our current model of AMPK trafficking proposes that the kinase shuttles between the nucleus and the cytoplasm. Data from our group and others support this idea, as they demonstrated that the nuclear carrier Crm1 is essential for AMPK export from the nucleus to the cytoplasm (Kazgan et al., 2010; Kodiha et al., 2007).
How the β subunit impacts the proper targeting of the holoenzyme is at present not entirely clear. The β1 subunit can be modified posttranslationally, both by phosphorylation and myristoylation, and these modifications were linked to the subcellular targeting of the β1 subunit (Suzuki et al., 2007; Warden et al., 2001). It was proposed that AMPK concentrates in the cytoplasm when the heterotrimeric enzyme contains the β1 subunit (Suzuki et al., 2007). However, this model is difficult to reconcile with the fact that both β1 and β2 subunits can be detected in the nucleus (Kodiha et al., 2007). Furthermore, recent studies suggest that the myristoylation of β1 and β2 subunit is particularly important for AMPK activation, as AMP-dependent myristoylation provides a switch that triggers Thr172 phosphorylation (Oakhill et al., 2010). Although the contribution of β subunits to nuclear and membrane targeting of the holoenzyme is not completely understood at this point, the importance of the β subunit for glycogen binding is well established (Polekhina et al., 2003).
In contrast to the α and β subunits, little is known about the trafficking of AMPK γ subunits. In Drosophila, the single γ subunit migrates into the nucleus of the fat body with the onset of autophagy during normal development, and a potential NLS was detected in this subunit (Lippai et al., 2008). It was speculated that this nuclear accumulation contributes to the expression of genes that are necessary for autophagy.
Several studies support the model that the intracellular distribution of AMPK in human and other cells is dynamic. This is particularly important in the context of disease, because the distribution of AMPK can be modulated by physiological and environmental stimuli. For example, the α2 subunit translocates to the cell nucleus upon exercise or environmental stress (Kodiha et al., 2007; McGee et al., 2003), indicating that the adaptation of skeletal muscle during exercise or metabolic stress is at least in part mediated by the subcellular relocation of AMPK. Examples of the relocation of AMPK α subunits in human cells exposed to oxidative stress or depleted for energy are shown in Fig. 4 (Kodiha et al., 2007).
The relocation of AMPK subunits in response to physiological changes is not restricted to the α subunits; our previous experiments demonstrated that AMPK β subunits accumulate in the nucleus as well when cells are exposed to oxidative and other forms of stress (Kodiha et al., 2007). Moreover, AMPK localization could be regulated by the circadian rhythm. Specifically, changes in the expression of AMPK subunits may depend on the circadian rhythm; this change in expression will then alter the intracellular distribution of AMPK (Lamia et al., 2009). Since these studies were carried out with mice, it has yet to be shown whether the same applies to humans.
Figure 4.
AMPKα concentrates in nuclei when cells are exposed to oxidative stress or depleted for energy. HeLa cells were treated with diethyl maleate to induce oxidative stress or with a combination of sodium azide and 2-deoxyglucose for energy depletion. The distribution of AMPKα1 and α2 subunits was examined by indirect immunofluorescence; DNA was stained with DAPI (Kodiha et al., 2007). Note that the α-subunits are more concentrated in nuclei of stressed cells. Several nuclei are marked with arrowheads. Size bar is 20 μm.
Studies from several laboratories, including our group, defined the signals and mechanisms that determine the trafficking and intracellular distribution of AMPK. Our work also suggested crosstalk between other signaling cascades and the localized action of AMPK (Kodiha et al., 2007 and unpublished). Ultimately, such crosstalk will add to the complexity of downstream events that are modulated by AMPK. Taken together, previous research suggests that AMPK subunits move between different subcellular locations, and it can be expected that the compartment-specific actions of the kinase are linked to the physiological response of cells and tissues.
4.3. How does the compartment-specific action of AMPK impact cellular functions that are relevant to type 2 diabetes?
Type 2 diabetes is associated with the increased risk of a growing number of diseases and pathologies. This is exemplified by renal nephropathy, myocardial disease, stroke, Alzheimer’s and Parkinson’s disease (Almdal et al., 2004; Biessels et al., 2006; Burdo et al., 2009; Hallows et al., 2010; Hu et al., 2007; Maher & Schubert, 2009; Schernhammer et al., 2011). Several drugs are currently used in the clinical setting to activate AMPK in patients suffering from type 2 diabetes or obesity. However, it should be kept in mind that AMPK activation can be beneficial as well as harmful in the ischemic heart, and AMPK activation may be linked to neurodegeneration (Lopaschuk, 2008; Spasic, Callaerts & Norga, 2009; Thornton et al., 2011; Vingtdeux et al., 2011). Thus, activation of AMPK throughout the whole organism or the entire cell of a particular tissue may not always be advantageous. As an alternative approach, we put forward the concept of a compartment-specific modulation of AMPK action. Since AMPK activation can be damaging in the context of some of the complications associated with type 2 diabetes, our approach applies both to the localized activation as well as inhibition of the kinase. We believe that the confined action of AMPK will provide a better therapeutic approach in the future that could reduce the side-effects of AMPK modulators. The simplified model in Fig. 5 summarizes the possible changes of cellular functions that will be induced by targeting AMPK in different subcellular compartments.
Figure 5.
Localized modulations of AMPK activity. The possible changes induced by the compartment-specific alteration of AMPK activity are depicted. Note that there are cell-type dependent differences for the processes regulated by AMPK.
In the past few years, significant progress has been made with the identification of AMPK substrates and their links to human disease. As shown in Fig. 3 and Table 3, AMPK modifies targets in different subcellular compartments or organelles. We propose that the modification of these substrates relies on (a) the amount of active AMPK and (b) the intracellular distribution of AMPK. The combination of AMPK activation and subcellular localization will then determine the level of phosphorylation of its substrates and the subsequent changes in cell physiology. Such changes will affect both the rapid response to specific stimuli as well as the long-term modification of metabolism and other processes. In the following, we focus on some of the processes that are controlled by AMPK and linked to type 2 diabetes or the complications associated with the disease.
4.3.1. AMPK targets the protein synthesis apparatus in the cytoplasm
Several of the cytoplasmic substrates of AMPK are essential to promote a fast cellular response to changes in nutrient supply. For example, AMPK phosphorylates cytoplasmic targets, such as eEF2 kinase and mTOR, which regulate protein translation. AMPK-dependent modification of these substrates results in downregulation of protein synthesis. Under some conditions, it could be desirable to preferentially modulate these processes that are associated with cytoplasmic AMPK targets. A possible example of such a scenario is the diabetic kidney (Cammisotto et al., 2008; Hallows et al., 2010; Lee et al., 2007; McMahon et al., 2009). Diabetes-induced renal hypertrophy correlates with diminished AMPK activity and, at the same time, with increased protein synthesis under high glucose conditions (Hallows et al., 2010). AICAR and metformin reduce protein synthesis triggered by high glucose (Lee et al., 2007), but these compounds also produce effects that are unrelated to AMPK activation (Mantovani & Roy, 2011). Thus, stimulating AMPK in the cytoplasm could provide a more focused approach to reduce damage in the diabetic kidney.
4.3.2. AMPK targets associated with the plasma membrane and vesicular trafficking
Several channels and transporters in the plasma membrane are phosphorylated by AMPK and control the secretion of insulin, hyperpolarization of β-cells under low glucose concentration and the response to hypoxia (Beall et al., 2010; Chang et al., 2009; Düfer et al., 2010; Evans et al., 2009; Hallows, 2005; Zheng et al., 2008). Although details of the molecular mechanisms are not always clear and in part controversial, altering the AMPK activity at the plasma membrane has the potential to modify β-cell function. The same principle could also apply to the heart and kidney, where several integral proteins of the plasma membrane are modified by AMPK.
4.3.3. AMPK substrates in the nucleus
In the nucleus, AMPK directly regulates the transcription of genes that control metabolism as well as the biogenesis of mitochondria and ribosomes. As such, AMPK modifies HNF4α, HDAC5, p300, histone H2B, the tumor suppressor p53, PGC1α, and TIF-1A (see Fig. 3 and Table 3). AMPK-dependent phosphorylation of these targets is critical to alter the transcriptional profile, which in turn is necessary to adjust metabolic activities in skeletal muscle, heart, liver and adipose tissues in response to changes in glucose availability. It is reasonable to assume that the modification of transcription factors and transcriptional regulators will rely to a large extent on AMPK in the nucleus. This model is supported by a recent study that shows AMPK to move along genes together with the transcriptional machinery (Bungard et al., 2010). Activation of AMPK in the nucleus could enhance the effects of AMPK on the transcription of several target genes. One of the possible benefits of the activation of nuclear AMPK will be the increase in mitochondrial biogenesis. In the long-term, this could help to stimulate the oxidation of fatty acids and limit the lipotoxicity that is linked to type 2 diabetes (Schrauwen & Hesselink, 2004).
4.3.4. AMPK targets associated with mitochondria
Acc2 is associated with mitochondria and important for the synthesis of malonyl-CoA, an intermediate of fatty acid biosynthesis. AMPK phosphorylates and thereby inactivates Acc, which leads to a reduction in malonyl-CoA concentration. As a consequence, de novo fatty acid synthesis is reduced and fatty acid oxidation is upregulated. It is conceivable that the localized Acc2 inhibition by AMPK could stimulate CPT-1 (carnitine palmitoyltransferase-1) dependent transport of fatty acids into mitochondria for subsequent degradation. This in turn could reduce the load of peroxidation products of fatty acids in the cytoplasm and the subsequent damage to mitochondria (Schrauwen & Hesselink, 2004).
5. Development of drugs that alter the compartment-specific activity of AMPK
In order to modulate AMPK activity in a fashion that is more localized as compared to the currently used drugs, a number of questions will have to be addressed. This includes the ability to regulate AMPK (a) in different organs or tissues and (b) in specific subcellular locations. Oral administration of metformin is believed to preferentially alter liver metabolism, whereas TZDs and their derivatives affect adipose tissue, skeletal muscle and probably β-cells (Gruzman et al., 2009). One possibility to enhance the tissue-specific action of AMPK will rely on the development of drugs that directly bind to AMPK; indeed such compounds have been described (Hawley et al., 2010). Since tissue-specific differences in AMPK subunits have been established, developing compounds that preferentially interact with individual subunits or specific subunit combinations of heterotrimers could provide a means to increase the specificity of AMPK action. For example, the γ3 subunit is predominantly synthesized in glycolytic skeletal muscle and could therefore serve as a target to alter AMPK in this tissue.
Taking into account differences in AMPK subunits could further be exploited to regulate the kinase in different subcellular locations (see section 4.2). Thus, it is believed that the α2 subunit is more concentrated in the nucleus as compared to the α1 subunit; this difference could help to activate mainly nuclear or cytoplasmic pools of the kinase. This line of reasoning could be expanded to the posttranslational modifications of the β subunit, as phosphorylation and myristoylation of the β subunits are implicated in the subcellular distribution of the kinase.
In addition to taking advantage of the differences in AMPK heterotrimers, developing AMPK modulators that accumulate in distinct subcellular compartments will be useful. This strategy could be based on the generation of combimolecules with multiple properties (Rachid et al., 2007). Combimolecules that combine DNA-binding with AMPK activation could enhance the modification of nuclear substrates and thereby alter the gene expression profile. On the other hand, such combimolecules could exploit the differences in lipid composition of intracellular membranes to control the AMPK-dependent phosphorylation of mitochondrial Acc2 or channels residing in the plasma membrane.
6. Conclusions
AMPK and its substrates are critical to the etiology and pathology of type 2 diabetes and other metabolic diseases. Several of the current therapeutic regimens for type 2 diabetes alter AMPK activity, either by affecting the cellular energy status or the concentration of AMPK modulators. More recent studies led to the identification of compounds that directly bind AMPK and change its enzyme activity. We propose that the future design of drugs that takes into account the dynamic subcellular distribution of the kinase and its substrates will help to regulate AMPK not only in different tissues and organs, but also at the subcellular level. In the long term this approach will help to fine-tune AMPK action and the downstream events that rely on the phosphorylation of its targets.
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Introduction",level:"1"},{id:"sec_1_2",title:"1.1. AMPK activity is critical to cell physiology in different tissues and organs",level:"2"},{id:"sec_3",title:"2. Organization and activation of AMPK",level:"1"},{id:"sec_3_2",title:"2.1. Control of AMPK activity by phosphorylation and changes in AMPK concentration",level:"2"},{id:"sec_4_2",title:"2.2. Pharmacological compounds and other factors that alter AMPK activity",level:"2"},{id:"sec_6",title:"3. AMPK functions in different tissues and organs",level:"1"},{id:"sec_7",title:"4. AMPK modulates targets in different subcellular organelles and compartments",level:"1"},{id:"sec_7_2",title:"4.1. Subcellular distribution of AMPK substrates",level:"2"},{id:"sec_8_2",title:"4.2. Subcellular distribution and trafficking of AMPK",level:"2"},{id:"sec_9_2",title:"4.3. How does the compartment-specific action of AMPK impact cellular functions that are relevant to type 2 diabetes?",level:"2"},{id:"sec_9_3",title:"4.3.1. AMPK targets the protein synthesis apparatus in the cytoplasm",level:"3"},{id:"sec_10_3",title:"4.3.2. AMPK targets associated with the plasma membrane and vesicular trafficking",level:"3"},{id:"sec_11_3",title:"4.3.3. AMPK substrates in the nucleus",level:"3"},{id:"sec_12_3",title:"4.3.4. AMPK targets associated with mitochondria",level:"3"},{id:"sec_15",title:"5. Development of drugs that alter the compartment-specific activity of AMPK",level:"1"},{id:"sec_16",title:"6. Conclusions",level:"1"}],chapterReferences:[{id:"B1",body:'AlmdalT.ScharlingH.JensenJ. S.VestergaardH.2004The Independent Effect of Type 2 Diabetes Mellitus on Ischemic Heart Disease, Stroke, and Death: A Population-Based Study of 13 000 Men and Women With 20 Years of Follow-up.Arch Intern Med\n\t\t\t\t\t16414221426'},{id:"B2",body:'AmatoS.LiuX.ZhengB.CantleyL.RakicP.ManH. 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Farney",authors:[{id:"48399",title:"Dr.",name:"Richard",middleName:"J",surname:"Bloomer",fullName:"Richard Bloomer",slug:"richard-bloomer"},{id:"50024",title:"MSc.",name:"Cameron",middleName:null,surname:"McCarthy",fullName:"Cameron McCarthy",slug:"cameron-mccarthy"},{id:"50025",title:"Mr.",name:"Tyler",middleName:null,surname:"Farney",fullName:"Tyler Farney",slug:"tyler-farney"}]}]}]},onlineFirst:{chapter:{type:"chapter",id:"75805",title:"Naturally Derived Carbon Dots as Bioimaging Agents",doi:"10.5772/intechopen.96912",slug:"naturally-derived-carbon-dots-as-bioimaging-agents",body:'
1. Introduction
The term ‘imaging’ is a perception that it is a type of photography; however, it is far from the biomedical domain. Bioimaging provides the anatomical visualization of cellular, subcellular structures, tissues, organs of multicellular organisms [1]. The biomedical imaging modalities utilize the various kind of energy sources such as light, magnetic resonance, positrons, ultrasound, electrons, and X-rays. The broad range of medical imaging modalities includes fluorescence (FL); X-ray computed tomography (CT), magnetic resonance (MR), ultrasound (US), positron emission tomography (PET) and single-photon emission computed tomography (SPECT) for diagnosis of various soft tissues and hard tissue pathologies and scientific research [2]. These techniques disclose the three-dimensional molecular information of any specimen’s biological structures and physiological processes.
Optical imaging, predominantly FL imaging modality received special attention from all the imaging modalities due to their simple operation process, cost-effective armamentarium, excellent resolution, incredible sensitivity and high resolution [3, 4, 5]. Therefore, a wide range of fluorescent imaging probes has been discovered for FL imaging, such as organic dyes, semiconductor quantum dots, metal nanocluster and up-conversion nanoparticles [3, 4, 6]. Nevertheless, their limitations include high toxicity, complicated synthesis mechanisms, poor water-solubility and high cost. On the other hand, single-mode fluorescence imaging techniques were limited to depth penetration and difficulty to provide tomographic information due to light attenuation and photon scattering of biological tissue. Therefore, developing FL based multimodal imaging by integrating other imaging modalities with FL imaging modality has become an essential strategy to resolve the single mode FL imaging limitations. Interestingly, FL based multimodal imaging provides several advantages including non-invasive imaging visualization with superior depth penetration, higher sensitivity and resolution [7]. Hence, it is necessary to develop a single probe by integrating other contrast agents with fluorescent materials for FL-based multimodality imaging applications.
Nanotechnology advancements in contrast agent development are progressing rapidly either by doping/incorporating or conjugation of other contrast elements into/with fluorescent nanomaterials to obtain a multimodal imaging probe [8]. Among the various types of nanomaterials, carbon dots (CDs) gained remarkable attention due to their significant physical, chemical and biological properties [9]. The integration of several unique properties in single nanosize carbon dots (CDs), make them ideal alternative material to replace the semiconductor quantum dots, metallic nanomaterials and other forms of carbon materials in various fields. Specifically, bioimaging, drug delivery, phototherapy, anti-microbial agents, sensors, solar cells, light-emitting diodes and photocatalysis [10, 11, 12, 13]. Specifically, CDs show significant potential in fluorescence-based multimodal imaging in vivo and in vitro. For example, FL/MR dual-modal imaging was developed by integrating iron oxide nanomaterials or doping Gd3+ or Mn2+ ions into CDs. Similarly, FL/PA, FL/CT and FL/PET etc., established by incorporating respective contrast agents. This book chapter initially discusses the top-down, bottom-up and green synthesis procedures of CDs, optical properties, and elemental doping and surface functionalization. Next, the bioimaging, importance of carbon dots application in the various medical imaging techniques, and therapeutic applications of carbon dots together as theragnostic are described. Finally, the outlook of carbon dots in bioimaging is mentioned.
2. Synthesis methods of carbon dots
In 2004, during the purification process of single-walled carbon nanotubes (SWCNTs) using gel electrophoresis, the CDs were discovered [10]. Later, various procedures established for the synthesis of CDs. Broadly, the CDs synthesis methods can be classified into as “top-down” and “bottom-up” approaches (Figure 1).
Figure 1.
Synthesis methods of carbon dots.
2.1 Top-down method
In the “top-down” approach, the breakdown of bulk carbon materials into nano size carbon occurs under relatively harsh conditions such as oxidative acid treatment, electrochemical exfoliation, laser ablation, and arc discharge [14]. The first described CDs were produced by the top-down process via laser ablation of graphite in the gaseous phase, subsequently acid oxidative treatment [15]. Later, numerous methods such as arc discharge, etching, electrochemical oxidation, ultrasonication, chemical exfoliation, and nitric acid/sulfuric acid oxidation developed to obtained CDs by reducing the size of bulk carbon materials [14, 16]. Mostly, graphite, graphene or graphene oxide (GO) sheets, carbon nanotubes (CNTs), carbon fibers and carbon soot etc. used as a precursor material in these methods. Even though these methods were successfully used to prepare CDs, they are limited with harsh conditions, complicated synthesis strategies, low quantum yield, expensive, eco-unfriendly, and unsuitable for the production of CDs in industrial-scale. These methods rarely used for the preparation of CDs from natural sources.
2.1.1 Bottom-up method
In the “bottom-up” approach, the CDs are synthesized from carbon-containing small molecules in a “polymerization– carbonization” process. Several methods include combustion, hydrothermal, solvothermal, and microwave-assisted pyrolysis developed in bottom-up synthesis [16]. Typically, in these methods carbon precursor such as small organic molecules taken in a liquid or gas stage are ionized, dissociated, sublimated or evaporated and then condensed via condensation, carbonization, polymerization and passivation to form nanosize CDs. Compared with the “top-down” strategy, the “bottom-up” approach is extensively used for the green synthesis of CDs using natural renewable sources. Here, we discussed some important synthesis methods of CDs.
Acid oxidation: In this method, CDs were synthesized by exfoliation and cleaving of activated carbon, graphene oxide, carbon nanotubes, carbon fibers and soot etc. by using concentrated acids such as sulfuric acid and nitric acid [17, 18]. Typically, this method involves the decomposing of the bulk carbon into nanoparticles and simultaneously introducing hydrophilic groups on the carbon core. Generally, these raw materials are low in cost, readily available and feasible for simple operation. This method can be extended for the synthesis of hetero atom doped carbon dots. For example, the heteroatom N doped CDs prepared using activated carbon as precursor and Nitric acid as oxidizing agent [19]. However, this method limited with some disadvantages such as harsh conditions and time-consuming process to eliminate excessive acid.
Electrochemical exfoliation: This is a facile green and large-scale approach in which, CDs were prepared by avoiding excess concentrated acid, complex separation and purification process [20, 21]. In this method, high purity graphite used as anode and Pt wire used as a counter electrode. Distilled water can be used as electrolyte but the rate of reaction is very slow. In order to increase the rate of reaction, ionic liquids like 1- butyl-3 methylimidazolium tetrafluoroborate and 1-butyl 3-methylimidazolium hexafluorophosphate can be mixed with distilled water and can be used as electrolyte [22]. The electrochemical exfoliation carried by applying static potential through direct power which leads to corrosion of graphite anode and hence formation of CDs. The mechanism involves releasing carbon dots because of the electrochemical scissors OH− and O− ions from the water’s anodic oxidation. Depending on the type of electrolyte nitrogen, phosphorus or boron can be doped in carbon dots.
Laser ablation method: The term ablation refers to the removal of surface atoms. Laser ablation method involves the absorption of highly energetic laser pulse by the carbon precursors and stripping of electrons from the atoms through a process like photoelectric effect generating a high electric field. Production of CDs takes place due to the repulsive force generated between positive ions and solid material [23, 24]. The size of the CDs can be controlled by a laser furnace. The precursors for laser ablation method are toluene, bulk graphite, graphene oxide and graphite powder etc. Laser ablation method provide high quality product with great velocity depending on the purity of the target and ambient media (gas or liquid). The size and other properties of carbon dots were controlled by irradiation time and laser fluence. The limitations of the method are requirement of high input energy and sophisticated equipment.
Ultrasonic treatment: In this green synthetic method, carbon materials can be broken down by the action of very high energy of ultrasonic waves [25, 26]. Ultrasonic waves create high pressure and low-pressure waves in liquid medium resulting in the formation, growth and violent collapse of small vacuum bubbles. The collapse of the bubbles lead to local high temperature and pressure up to 5000 K and 1000 atm respectively, producing the CDs. The precursors used for making CDs in this method are crab shell powder, glucose, active carbon, polyethylene glycol, citric acid, tri-ammonium citrate, and arginine. N, S, and P elements doped CDs can also be prepared by this method.
Microwave synthesis: This method involves the irradiation of electromagnetic radiations within a range of 1 mm to 1 m through the carbon precursor containing reaction mixture, which results from rapid and uniform heating. The microwaves absorbed by the solvent and precursor leading to the activation of molecules directly and its leads to formation of CDs [27, 28]. So, reaction volumes as such as 200 μl to >100 ml can be used without difficulty. The advantages of microwave irradiation are fast, higher efficiency and require less purification. The microwave irradiation can be controlled instantaneously so the risk of overheating is also minimized. However, the main drawback of this method is that solvents with lower boiling point cannot be used. This method widely used to convert bio-waste and natural sources such as plant materials, sea food waste and kitchen waste into CDs [29, 30, 31].
Thermal decomposition: In ordinary thermal decomposition, a carbon containing compound or substance decomposes chemically by action of heat and converted into CDs [32]. In general, CDs were synthesized from the variety of precursors like citric acid and L-cysteine etc. by simple heating under pyrolytic condition and controlled pressure using ionic liquid like 1-butyl 3-methyl imazonium bromide [33, 34]. The advantages of ionic liquid are high thermal stability, chemical stability; low melting point and low vapor pressure. At very high temperature, an irreversible thermal decomposition of organic matter takes place in inert mixture. Low cost, easy to operate, less time consuming and large-scale production are the advantages of the thermal decomposition method.
Pyrolysis: Pyrolysis is an irreversible thermal decomposition reaction in which decomposition of organic materials take place in inert atmosphere and at high pressure. Pyrolysis of the carbonaceous material is a simple, clean and inexpensive route for synthesizing CDs because no need of additives, acids or bases [35, 36]. In this method, solid residues with high carbon content were formed from organic materials by prolonged pyrolysis in an inert mixture. During pyrolysis, dehydration and fragmentation occurs. The natural precursors used for producing CDs in this method are cheap biowaste materials like rice husk, coffee grounds, watermelon peel, sago waste, peanut shells and wool etc.
Hydrothermal or solvothermal synthesis: In hydrothermal synthesis, carbon precursors undergoes “polymerization–carbonization” and leads to formation of CDs in water media taken in a sealed container under high temperature and pressure [37]. In solvothermal synthesis, organic solvents like methanol, ethanol, n-butanol and N, N- dimethylformamide etc. can be used as the solvent instead of water [38, 39]. This method was proved to be a cheap and eco-friendly route to the synthesis of carbon dots. However, solvothermal reactions can lead to an explosion in a few cases because the temperature rises rapidly in limited space. This can be avoided by taking a small quantity of solvent and reactant.
2.1.2 Natural materials as a green precursor for preparation of CDs
The green synthesis of CDs relies on natural precursors such as plant materials, protein products and waste materials [40]. Compared with bulk carbon materials (Graphene, Graphene Oxide and carbon tubes etc.) and toxic organic compounds including aromatic molecules, natural materials are renewable, economical, eco-friendly, safer and easier to get industrial-scale production. Mostly, “bottom-up” methods adopted for the synthesis of CDs due to the existing small organic molecules in natural sources can be carbonized into CDs at a specific temperature. A few top-down methods developed for the waste bulk carbon materials or bio-waste are broken down/cut into small-sized CDs. Among the various techniques, hydrothermal and microwave approaches are extensively used to prepare CDs from multiple natural materials. Most natural sources or biomass materials are made with small organic molecules, converted into CDs by carbonization and pyrolysis.
In recent years, various kind of plant material such as coriander leaves, ginger, garlic, grass, coffee beans, lemon, orange juice etc. due to the existence of various carbon containing organic molecules including carbohydrates, cellulose and phenolic compounds [41]. Compared with commercial precursors, the plant material derived CDs showed enhanced fluorescence emission with high quantum yield due to heteroatoms such as nitrogen, sulfur and phosphorus. Hence, the optical and structural properties of CDs are mainly relying on the selection of natural precursors. Besides this, with the growing concern about environmental pollution and sustainability, variety of waste materials including different kind of agriculture, kitchen, fruit peel and seafood waste etc. used as a starting material for the preparation of CDs [30, 42, 43]. These waste resources, also containing organic molecules, can be polymerized and followed by carbonized to form CDs.
2.2 General properties
The general properties of CDs illustrated in Figure 2. Structurally, CDs belongs to the quasi-spherical zero-dimension carbon nanomaterials class with a size of less than 10 nm [44, 45]. They are amorphous or nanocrystalline cores with a typical sp2 carbon hybridization. The absorption band of CDs exhibits UV–Visible region to the NIR region and contains various functional groups. The electrifying properties of CDs are their excitation wavelength-dependent emission spectrum, high photostability and resisting to photobleaching, which permits CDs for multicolour and long-term imaging applications, respectively [45]. The cytotoxicity and preclinical biocompatibility of CDs on various models such as cell lines, zebrafish, mice displayed CDs have no apparent toxic effects. Extensive studies are to be done on the toxicological and biocompatibility properties to translate from preclinical to clinical application. For targeted bio-imaging, the surface functional groups such as hydroxyl, amine and carboxylic groups allow conjugation with targeting agents.
Figure 2.
Properties of carbon dots.
2.2.1 Optical properties
Among all the CDs’ properties, optical properties such as absorbance and fluorescence are vital for bio-imaging applications [45, 46]. Usually, CDs exhibited a strong absorption band at UV region with a falling intensity absorption tail increased to the visible light region. Usually, absorption peak around 230–340 nm was typically ascribed due to π-π* transition of the C=C bonds of the carbon core. Similarly, the absorption band of 350–550 nm is ascribed to the surface functional groups on the carbon core. Besides this, one exciting feature of CDs is their excitation wavelength-dependent emission spectrum by varying excitation light wavelength, which is commonly observed in most CDs, which allows for multicolour imaging applications. CDs’ exact PL mechanism is currently debatable due to the various methods available for the preparation of CDs and the lack of consistency in CDs’ PL behavior. Nevertheless, three main mechanisms have been proposed to explain the PL of CDs: (1) The intrinsic band gap arising from the quantum confinement effect or the conjugated π domains, determined by CDs carbon core. (2) The creation of trap states (such as surface defects) in the band gap due to the surface functionalization and CDs doping. (3) The presence of individual fluorescent molecules (fluorophores) on or within the CDs. According to these theories, the wide tunable emissions of CDs have been attributed to their broad size distribution, variable surface chemistry, and the uncontrolled preparation conditions. Another fascinating PL property about CDs is that they generally exhibit high photostability, resisting photobleaching, which is very important for long-term imaging applications.
2.2.2 Elemental doping and surface functionalization
Usually, most of the bare CDs showed comparatively weak FL ability than traditional semiconductor quantum dots or organic dyes. In this line, CDs’ structure altered by incorporating elements or surface functionalization strategies to improve fluorescence properties which are essential for fluorescence-based bio-imaging applications. So far, a variety of element doping is adopted to obtain CDs with charming FL properties. At present, heteroatoms such as N, S, Si, P, B, Ga, halogen (Cl, Br, I), Se, Ge, Mg, Cu, Zn, Tb, Ru and Mn incorporated into CDs during the synthesis process [47, 48]. Besides this, large functional groups such as carboxylic acid, amine, hydroxyl and amide groups presence on the surface of CDs facilitate the opportunity to conjugate with various passivate agents [38, 49]. Therefore, several groups focused on improving the fluorescence efficiency through conjugation with variety of passivating agents such as Polyethylene glycol, polyethyleneimine, poly (propionyl ethyleneimine co-ethyleneimine), 4,7,10-trioxa-1,13-tridecanediamine, 1-hexadecylamine, poly(ethylenimide)-b-poly(ethyleneglycol)-b-poly (ethylene imide) and amino acids etc. Generally, these passivating conjugate with CDs via electrostatic interactions, covalent bonds, and hydrogen bonds. More interestingly hetero element doped or surface modified CDs also improved water solubility, photostability, biocompatibility, NIR absorbance and multicolour fluorescence emission, which are the vital parameters for bioimaging. Moreover, unique surface functional CDs have been prepared based on individual cell membrane lipids, proteins, targeting ligands and biomarkers of different cells to develop impactful imaging applications. Furthermore, variety of targeting moieties including peptides (transferrin), aptamers, antibodies and small molecules (folic acid) which have been selected to integrate on the surface of CD through N-hydroxy succinimide (NHS) or 1- ethyl-3-(3-dimethyl-aminopropyl) carbodiimide hydro-chloride (EDC) chemistry [50]. These targeting moieties offer the internalization of CDs into cells or tissues via a ligand-receptor interaction. Remarkable specific cell targeting bioimaging besides adequate circulation of CDs avoid the side effects originating from the nonspecific interactions. The targeting moiety linked to CDs improves the specificity of bioimaging. Moreover, various cancer therapeutic drugs, anti-microbial agents and photosensitizers were conjugated with the CDs’ surface for image guided therapeutic applications.
3. Bio-imaging
Bioimaging is an emerging field of biomedical science that comprises of the development and application of various materials for imaging technologies [51, 52]. The bioimaging techniques principles are mainly based on optics, magnetic resonance, nuclear medicine, radiation, ultrasonics, photonics and spectroscopy. The anatomical and physiological quantification of clinical parameters is measured with the image processing and analysis. With the recent development of biomedical science and emerging newer technologies, the in vivo or ex vivo biological tissue characterization of imaging properties aids in discerning its structure and function through visualization at several resolutions, extending from organ and cellular to molecular level. FL, near IR CT, PET, MRI and ultrasound images are commonly used for clinical diagnosis and research (Figure 3). The characteristic ‘energy-matter’ interaction is utilized by most bioimaging techniques to provide precise particulars of the biological processes. The imaging modality’s uniqueness defines in terms of anatomical and molecular details, spatial and temporal resolution, depth of imaging and properties of contrast agents of augmented imaging. In many clinical scenarios, the application of multimodal imaging techniques is advantageous for a simultaneous, faster and more accurate diagnosis. Exogenous contrast agents which are used in many imaging modalities enhances the signal to noise ratio. So, the development of multimodal contrast agents is essential to achieve better efficacy and accuracy in diagnosis and therapeutics.
Figure 3.
Applications of carbon dots.
4. Importance of carbon dot in bio-imaging
For clinical imaging application, good biocompatibility and low cytotoxicity of imaging probes are essential. The traditional quantum dots (QDs) such as CdSe, CdTe, CdS, and PbS were applied in invitro and in vivo optical bioimaging procedures [53]. But their bioimaging application is restricted due to heavy toxic metals which may cause toxicological and pathological problems for health and the environment. The silicon quantum dots (Si QDs) can be considered alternatives to heavy metal QDs in bioimaging [54]. But they undergo oxidative biodegradation in biological systems and are slightly toxic. The gold and silver nanoclusters were deemed to be alternative, non-toxic, photo luminescent nanomaterials, but suffering with poor water solubility and photostability [55]. So, there is a requirement for biocompatible imaging probes with low toxicity for bioimaging. Some CDs such as low toxicity, good biocompatibility, excellent photoluminescence and high photo stability makes them a novel nanoprobe for bioimaging.
4.1 Fluorescence imaging
FL imaging is a promising technique for observing and assessing various cells, tissues and organisms, by the high fluorescence emission with biocompatible fluorescent agents [56, 57]. Currently, fluorescent CDs are considered as a significant alternative ideal contrast agent for fluorescence imaging. Several reports revealed that cells incubated with CDs emitted fluorescence mainly due to accumulation of CDs in the cells. Generally, unmodified/bare CDs are majorly identified in the cell membrane and cytoplasmic region without reaching the nuclei. To resolve this issue, excessive effort have been devoted to surface modify the CDs with targeting agents including antibodies, peptides and other biomolecules to enhance the specific targeted bioimaging. These target ligands modified CDs showed a significant capacity to bind to the overexpressed reprehensive receptor/biomarker on cells. In addition, to resolve the issues related to deep tissue fluorescence imaging, the NIR receptive CDs were designed with longer excitation/emission wavelengths that enhanced fluorescence imaging ability [58] for in vivo applications. Under suitable excitation wavelength the NIR emitting CDs can be well differentiated from the auto-fluorescence background (green) with good optical contrast.
4.2 Multimodal imaging
Every imaging technique has its unique advantages in consort with integral limitations such as insufficient sensitivity or spatial resolution (Figure 4) [59]. Even the fluorescence imaging provides high sensitivity but lacks of sufficient resolution. To compensate this drawback, the combination of fluorescence imaging techniques with other modalities, such as FL/MRI has gained attention to enhance the currently used imaging techniques for diagnosis [58]. Multimodal imaging is a combination of two or more imaging techniques to overcome individual limitations. The development of multi-modality imaging with the FL imaging is to achieve non-invasive imaging at greater depths of penetration, sensitivity and higher resolution required for an accurate diagnosis. Thus, optical imaging assisted multi-modalities has emerged as potent tools, which can improve the detection sensitivity, precise identification and provide more detailed anatomical or biological information of the pathology. Each imaging technique uses different contrast agents with distinctive functional, chemical compositions and sizes. In designing and developing a multi modal contrast agent, the researchers should judiciously forbid the overlay of pros and somewhat counterbalance each modality’s limitations to enhance the synergistic effect. Thus, the FL imaging modality with high sensitivity is frequently combined with other imaging modalities with a high spatial resolution modality such as MR, CT, and PA etc. (Figure 5). Hence, multimodal contrast agents’ development and application are clinically significant for enhanced imagery from desirable imaging modality. Multimodal imaging agents based on fluorescent CDs are the recent cutting-edge technologies where CDs’ advantages are maximized. CDs based multimodal imaging agents are prepared by conjugating or incorporating one or more imaging agents into CDs. Here we have discussed various kinds of fluorescent CDs’ based multi-modality imaging approaches such as FL/PA, FL/MR and FL/CT imaging.
Figure 4.
Advantages and disadvantages of various imaging techniques.
Figure 5.
Carbon dots integrated multi-modal bio imaging.
4.2.1 Fluorescence/photoacoustic imaging
Photoacoustic (PA) imaging is a non-invasive, hybrid, optical and ultrasound imaging modality. The PA imaging is performed at varying depths with high depth to resolution ratio with rich optical contrast beyond the optical detection limit. The CDs have shown significant PA imaging application because of the NIR absorption, high extinction coefficient, and non-radiative heat generation. Wang, et al. synthesized dual-mode FL/PA imaging agent based on CDs [60]. Within the NIR spectrum, the imaging agent exhibited a maximum optical absorption at 710 nm approximately. In in vivo PA imaging of mice tumor model, enhancement of signal and clear demarcation of the tumor was observed due to long circulation time and increased tumor accumulation of CDs. Hence, the combination of fluorescence and photoacoustic imaging into a single probe based on CDs enabled deeper tissue penetration for tumor identification. Compared with single optical imaging, the dual-mode FL/PA imaging upholds the sensitivity and provides higher-resolution anatomical images. Porphyrin implanted CDs developed by selective pyrolysis with good aqueous dispersibility displayed a strong PA signal at 686 nm in a slightly acidic or neutral environment and somewhat alkaline conditions pH 7–8 the signal was weak [61]. In breast cancer, the sentinel lymph nodes detection, the application of photo acoustic visualization of CDs was reported by Wu, et al. [62]. After injection the CDs exhibited rapid signal enhancement and relatively fast clearance from the lymph nodes.
4.2.2 Fluorescence/magnetic resonance imaging
Magnetic resonance imaging (MRI), is a radiation-free and non-invasive imaging technique widely used to detect various diseases including clinical cancer diagnosis and therapeutic response assessment [63]. With an external radiofrequency pulse magnetic field applied on the body, it simultaneously obtains anatomical and physiological information of regions of interests with a high spatial resolution by manipulating magnetic nucleus’s resonance (1H). Further, the integration of FL imaging with MR imaging considered as most effective non-invasive imaging tool in diagnosis and clinical research due its excellent spatial resolution, high temporal and sensitivity. Hence, the CDs assisted FL/MR dual modality potentiality can take benefits of the spatial resolution, outstanding soft-tissue contrast with MR imaging as well as superior sensitivity and the rapid data acquiring with FL imaging. This dual imaging modality is facilitated precise diagnosis with effective treatment based on corresponding imaging evidence. The CDs-relayed FL/MR dual-mode imaging modality probe can be obtained by the doping/ conjugation of magnetic elements. Specifically, extremely paramagnetic ions including Gd3+, Mn2+, and Fe3+ employed as dopant for the preparation of FL/MR bimodal contrast agent such as Gd or Mn elements into CDs. For example, Gd3+ doped CDs were synthesized from Gd3+ containing precursors and sucrose as carbon precursors via microwave assisted method polyol by Gong Ningqiang, et al. The attained Gd-CDs showed green fluorescence emission, low cytotoxicity and optically label cells. Meanwhile, the r1 relaxivity of Gd-CDs was measured to be 11.356 mM−1 s−1. This high r1 value together with the r2/r1 ratio approximately 1. These results indicating that Gd-CDs is not only significant fluorescent imaging agent but also remarkable T1 contrast agent for MR imaging [64].
Further, Jia Qingyan, et al. demonstrated the magneto-fluorescent Mn-doped CDs for bimodal FL/MR imaging in a single probe. The study reported the development of ultrafine Mn-doped CDs with a concurrent bimodal imaging ability through the solvothermal procedure of the precursor manganese (II) phthalocyanine [65]. The Mn-doped CDs showed strong T1-weighted MRI signals and low cytotoxicity. The MRI signal intensities increased with the concentration, exhibiting a clear difference in brightness with a measured relaxation (r1) value of ≈6.97 mM−1 s −1. Furthermore, the in vivo T1-weighted results fortified the high retention rate of the Mn-doped CDs in tumors. The MRI signal intensity at the tumor site increased quantitatively by ≈320%, after 6 hrs injection while the MRI signal remained nearly unchanged for the analogous CDs without manganese (II) doping. CDs doped with dysprosium for a magneto-fluorescent bimodal imaging agent showed strong blue-green fluorescence at 452 nm. The excellent transverse relaxivity r2 makes them also suitable for T2 weighted imaging of live cells [66].
4.2.3 Fluorescence/X-ray computed tomography
X-ray computed tomography (CT) is a non-invasive medical imaging technique for disease diagnosis. The CT has intrinsic advantages such as high spatial resolution and good density; it still has inherent drawbacks of low sensitivity. On the other hand, the fluorescence imaging has high sensitivity, facile operation and low cost, but its application was hampered due to the low spatial resolution and limited penetration depth. To improve clinical diagnostic accuracy and sensitivity, the FL and CT imaging are combined for a synergistic effect. The CDs doped with Hafnium (Hf) was used for diagnostic imaging of the orthotopic liver cancer preclinical model [67]. Rapid imaging was achieved with Hafnium doped CDs due to preferential tumor accumulation within 1 min. These imaging nanoprobes with efficient renal clearance offers good biocompatibility. Iodine doped CDs conjugated with a chemotherapeutic agent like cetuximab simultaneously rendered the cancer diagnosis and targeted anti-cancer therapeutic potential in lung cancer cells [68].
5. Imaging guided therapeutic application
Nanotechnology provides the possibility of developing non-toxic CDs nanoprobes with enhanced sensitivity, accuracy and advanced functionalities for imaging-guided synergistic therapy [69, 70]. The unique advantages of CDs include high relaxivity, prolonged blood circulation time, multiple functionalities for accurate accumulation in the target site, good biocompatibility and renal clearance. The inherent radio resistance of tumors and inaccurate positioning of the radiotherapeutic equipment leads to decreased radiotherapy effectiveness. Du Fengyi, et al. reported the theragnostic Gd-CDs with stable photoluminescence at the visible region, relatively long circulation time, efficient passive tumor targeting ability and renal clearance for MRI-guided radiotherapy a tumor [71]. Changhong Zhao et al. developed red-emitting wavelength multifunctional CDs for cancer theragnostic with in vivo bimodal imaging of tumor tissues and anti-cancer chemo-dynamic treatment (CDT). The functionalization of red CDs was done with Ethylene di amine tetra-acetic acid, Fe2+and Gd3+exhibited strong T1 weighted MR imaging and excellent bright and stable fluorescence. The anticancer CDT effect was based on Fenton reaction, by releasing Fe2+ into the tumor both invitro and in vivo [72].
6. Conclusions and outlook
Naturally, renewable sources derived CDs are kind of newly born luminescent carbon-based nanomaterials in this decade. They gained great potential in bio-imaging not only because of their cost-effective and eco-friendly green synthetic approaches but also their physical, chemical and biological properties. We have elaborately discussed various synthesis methods, significant properties. Furthermore, the recent development of CD in multimodal bio-imaging. Their strong fluorescence emission, high fluorescent quantum yield, and good absorbance are widely used for fluorescence imaging. Specific CDs also allow for multicolour bioimaging due to their multicolour emission capability. Further, numerous surface functional groups provide an opportunity to conjugate with targeting moieties such folic acid for targeting imaging. Accordingly, CDs conjugation with targeted moieties can precisely transport imaging contrast agents to internal organelles or cell membranes to attain the goal of targeted bio-imaging. In the meantime, the large surface area of CDs permits them to have a more quantity of hetero atom loading ability, consequently showing remarkable multimodal imaging ability. Finally, the nano size of CDs (typically >10 nm) facilitates their navigation in tissues, endocytosis, and intracellular trafficking. Even though significant efforts have devoted to improving the multimodal imaging effect of CDs, several limitations hinder the application of CDs in bio-imaging. Primarily, the emission from most of the natural sources derived CDs showed blue or green, thus developing the methods and finding suitable natural precursor for yellow or red emissive CDs is highly desired. CDs exhibit excellent biocompatibility; however, majority studies are confined to cellular and preclinical experiments, but translation into clinical investigations is still unclear. In summary, more research still needs to be made for the effective and real-time clinical application of CDs in multimodal imaging.
\n',keywords:"carbon dot, bioimaging, fluorescence, theragnostic, contrast agent",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/75805.pdf",chapterXML:"https://mts.intechopen.com/source/xml/75805.xml",downloadPdfUrl:"/chapter/pdf-download/75805",previewPdfUrl:"/chapter/pdf-preview/75805",totalDownloads:40,totalViews:0,totalCrossrefCites:0,dateSubmitted:"July 26th 2020",dateReviewed:"March 1st 2021",datePrePublished:"March 19th 2021",datePublished:null,dateFinished:"March 19th 2021",readingETA:"0",abstract:"The recent advances in nanoscience and technology have opened new avenues for carbon-based nanomaterials. Especially, Carbon dots (CDs) have gained significant attention due to their simple, economic and rapid green synthesis. These materials exhibit excellent water solubility, fluorescence emission, high fluorescence quantum yield, Ultraviolet (UV) to Infrared (IR) range absorbance and high bio-compatibility. Therefore, these materials are widely used for various biological applications including bio-imaging. With the integration and doping of surface passive agents and elements, respectively influenced the enhancement of fluorescence property of CDs. Also, the conjugation of receptor-based targeting ligands leads to targeted bioimaging. CDs in combination with other imaging contrast agents lead to the development of novel contrast agents for bimodal imaging and multimodal imaging techniques. The combination of diagnostic CDs with therapeutic agents resulted in the formation of theragnostic CDs for image guided therapies. In this chapter, a comprehensive view on the top-down and bottom–up green synthesis methods for naturally derived CDs discussed. Further, unique physical, chemical, optical and biological properties of CDs described. Finally, fluorescence based bimodal and multimodal imaging techniques also described.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/75805",risUrl:"/chapter/ris/75805",signatures:"Gangaraju Gedda, Arun Bhupathi and V.L.N. Balaji Gupta Tiruveedhi",book:{id:"10301",title:"BioMechanics and Functional Tissue Engineering",subtitle:null,fullTitle:"BioMechanics and Functional Tissue Engineering",slug:null,publishedDate:null,bookSignature:"Prof. Ziyad S. Haidar, Dr. Ibrokhim Y. Abdurakhmonov and Dr. Abdelwahed Barkaoui",coverURL:"https://cdn.intechopen.com/books/images_new/10301.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-83880-286-8",printIsbn:"978-1-83880-285-1",pdfIsbn:"978-1-83880-417-6",editors:[{id:"222709",title:"Prof.",name:"Ziyad S.",middleName:null,surname:"Haidar",slug:"ziyad-s.-haidar",fullName:"Ziyad S. Haidar"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Synthesis methods of carbon dots",level:"1"},{id:"sec_2_2",title:"2.1 Top-down method",level:"2"},{id:"sec_2_3",title:"2.1.1 Bottom-up method",level:"3"},{id:"sec_3_3",title:"2.1.2 Natural materials as a green precursor for preparation of CDs",level:"3"},{id:"sec_5_2",title:"2.2 General properties",level:"2"},{id:"sec_5_3",title:"2.2.1 Optical properties",level:"3"},{id:"sec_6_3",title:"2.2.2 Elemental doping and surface functionalization",level:"3"},{id:"sec_9",title:"3. Bio-imaging",level:"1"},{id:"sec_10",title:"4. Importance of carbon dot in bio-imaging",level:"1"},{id:"sec_10_2",title:"4.1 Fluorescence imaging",level:"2"},{id:"sec_11_2",title:"4.2 Multimodal imaging",level:"2"},{id:"sec_11_3",title:"4.2.1 Fluorescence/photoacoustic imaging",level:"3"},{id:"sec_12_3",title:"4.2.2 Fluorescence/magnetic resonance imaging",level:"3"},{id:"sec_13_3",title:"4.2.3 Fluorescence/X-ray computed tomography",level:"3"},{id:"sec_16",title:"5. 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Department of Basic Science, Vishnu Institute of Technology, India
Department of Basic Science, Vishnu Institute of Technology, India
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