\r\n\tNotably, the book encourages academic scholars and researchers to contribute to the modern concepts of CSR. Fundamentally, it speaks for well-developed literature for entrepreneurs and managers, thus assisting them in the decision-making process. \r\n\tFurthermore, this book is of great value to policymakers, practitioners, and corporations, thus contributing to various disciplines (e.g., social science and management). \r\n\tThese proposed themes encourage future researchers and professionals to share their ideas, concepts and work concerning these subject domains. All these suggested topics had recommended under the rubrics of CSR. Perhaps, all the professionals, researchers, and scholars are welcome to submit their piece of work, in particular to the suggested topics. \r\n\tIndeed, the recommended topics include the following but are not limited to these only. \r\n\t• Corporate Governance and Sustainability \r\n\t• Green Innovation and CSR \r\n\t• Social Entrepreneurship \r\n\t• Green Economy and Social and Environmental Sustainability \r\n\t• Sustainable Development and Industrialization
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\n
1. Introduction
\n
\n
1.1. General aspects of liver disease and hepatic encephalopathy
\n
Liver disease is one of the leading non-infectious pathologies affecting people around the world. In its report from 2015, WHO indicates that the advanced form of liver disease, meaning cirrhosis, is among the 20 most frequent (2%) causes of death (~1.62 × 106) around the globe (http://www.who.int/). Hepatic encephalopathy (HE) is a pathological condition that represents the neuropsychiatric disorder derived from liver disease. It is known that about 80% of patients with liver disease (depending on severity), may develop HE, which represents one of the major complications leading to death in about 90% of patients with acute liver failure (ALV) [1]. HE has been classified by the Hepatic Encephalopathy consensus Group, at the World Congress of Gastroenterology in 1998, in type A, associated with ALV; type B related to porto-systemic bypass; and type C related with chronic liver disease, mainly cirrhosis [2]. Further classification includes the severity of symptoms that includes the subcategory called covert (CHE, also known as minimal), persistent (PHE), and overt (OHE). The former is mild in manifestations and is hard to diagnose without specific neurophysiological and neuropsychological tests, such as the visual-based flicker test, the psychometric hepatic encephalopathy score (PHES), the repeatable battery for assessment of neuropsychological status (RBANS), the inhibitory control test (ICT), the cognitive drug research (CDR), and the most recent STROOP App test (EncephalApp_Stroop), a practical smartphone App tool for HE screening to be used by the own patients [3, 4]. The PHE and OHE involve more specific clinical symptoms, including seizures, hyperreflexia, rigidity, myoclonus (sudden involuntary jerking of a muscle or a group of muscles), asterixis (hand tremor when wrist is extended), and stupor, which can be detected or reported by the clinician or patient as well [5]. In all of these cases, the main gross causative is the liver failure and the metabolic pathways affected thereafter. In general terms, HE is a debilitating condition in which patients gradually became less psychologically independent and more psychiatrically dependent. The majority of the symptoms in HE are triggered by molecular events within the central nervous system (CNS), and several hypotheses have been proposed in order to understand the pathophysiology. Some of them suggest that metabolites such as ammonia, myoinositol, glutamine, manganese, inflammatory mediators (IL-1, IL-6, and TNFα), and amino acids (Tyr, Phe, Val, Ile, and Leu) [6], regarding its effects over astrocytes and neuronal cells, are responsible of the clinical manifestations of the disease [6, 7, 8].
\n
\n
\n
\n
2. Astrocytes as mediators of the pathophysiology of HE
\n
In this and further sections, we will try to introduce to the reader into a review about recent findings that illustrates how the physiological functions of the liver, or to a better extent, a lack of them, may harm at different levels, the metabolic and physiological homeostasis over brain cells and function.
\n
\n
2.1. Ammonium metabolism
\n
The liver is responsible to detoxify the majority of endogenous or exogenous toxic compounds produced by the metabolic or catabolic activity within the organism, including pharmacological metabolites, ammonium, bilirubin, bile salts, etc. Several factors may affect liver functions, such as increased consumption of a fat diet, another one is the chronic alcohol abuse; while the infection by hepatitis C virus (HCV), pharmacological intoxication (mainly paracetamol), complete the pathological scenario. The fatty liver, also known as steatosis (non-alcoholic fatty liver disease or NAFLD), has been called the first hit in liver damage, which when not properly attended, could result in a chronic inflammation or steatohepatitis (NASH). NASH could evolve to fibrosis and eventually to a more critical stage, cirrhosis. Cirrhotic patients suffer a wide spectrum of comorbidities [9]. Among them is hepatic encephalopathy (HE), a debilitating psychological condition where the patients present a variety of symptoms including loss of memory, mild or manifested tremors, and most importantly, increased plasma levels of ammonia. In basal conditions, ureotelic organisms like humans, should contend with the ammonia derived from the gastrointestinal bacterial activity and muscle metabolism, by converting it to carbamoyl-phosphate (CP), a substrate of the urea cycle, CP is then converted to citrulline, the precursor of arginosuccinate; arginosuccinate is then transformed to arginine and by the action of arginase, arginine is converted to urea and ornithine; all of these reactions takes place within the mitochondria and cytosol of the hepatocytes, resulting in the release of urea into the bloodstream and then in urine [10]. However, in pathological conditions like cirrhosis, hepatocytes are unable to produce urea; therefore, ammonium in its form of gas (NH3) easily diffuses to the blood brain barrier (BBB). Once within CNS, ammonium is metabolized primarily by the astrocytes, a group of specialized glial cells capable of modulate inhibitory and excitatory neurotransmission. In its form of ion (NH4+), ammonia reaches the astrocytes where a different transporter mediates its translocation throughout the plasma membrane. Among this transporters are the Na+/K+-ATPase pump, the Na+/H+-ATPase antiporter and Na+/K+/2Cl−, K+/Cl− symporters [5]. Astrocytes metabolize the ammonium by the so-called glutamate-glutamine cycle (GGC). The GGC produces glutamine (Gln) through the action of glutamine synthetase (GS), delivering it to neighboring glutamatergic neurons (Figure 1). In neurons, glutamine is subject to the opposite reaction, mediated by the enzyme glutaminase, whose products are glutamate and ammonium. Glutamate is packaged into synaptic vesicles and released to the synaptic cleft in response to electrochemical stimulus, while ammonium is released to the extracellular space [11]. Once released, glutamate binds to ionotropic (N-methyl-d-aspartate (NMDA) or AMPA) receptors, or metabotropic (mGluR1 and mGluR2) receptors in the postsynaptic neuron and astrocytes [11]. Unbound released glutamate can be recycled when captured by the excitatory amino acid transporters (EAAT) located in the astrocytes membrane. These events represent the final step in the GGC.
\n
Figure 1.
The glutamine (Gln)-glutamate (Glu) cycle within astrocytes. Glutamine synthase (GS) mediates the reaction of ammonia (NH4+) and Glu to produce Gln. Gln is then exported by a specific transporter (illustrated here as a small black cylinder) to the glutamatergic neurons near the astrocyte. The cycle completes when Glu is released to the synaptic cleft and then binds to NMDA receptors or is recaptured by astrocytes to began the cycle. See text for details.
\n
On the other hand, besides GGC, astrocytes may use other systems to titrate ammonium from bloodstream. Those based in the use of the branched chain amino acids (BCAA) on one side, or the use of L-ornithine and L-aspartate in the other. In the first case, BCAA are metabolized by the enzyme branched-chain amino acid transaminase (BCAT) particularly enriched in the cytoplasm and axons of glutamatergic and GABAergic neurons [12]; cytoplasmic BCAT enzymatically mediates the synthesis of branched-chain ketoacids (BCKA), which in turn generates both, a precursor for the tri-carboxylic acid cycle (TCA) in the form of Acetyl-CoA and the excitatory amino acid glutamate; glutamate in turn, can be metabolized by means of the GS to produce glutamine; glutamine is deaminated by the phosphate-activated glutaminase (PAG) which is also present in the cytoplasm of neuronal and glial cells [13]. The second one, the L-Ornithine and L-Aspartate system, operates to generate glutamate by means of the ornithine- or aspartate-aminotransferase (OAT, AAT); both enzymes are enriched in the skeletal muscle, thus contributing to stimulate the glutamine production in this tissue by the GS, diminishing the ammonia derived from circulation [5]. L-ornithine and L-aspartate represent one of the most frequent therapeutic approaches to improve ammonia levels in cirrhotic patients, as we shall see later.
\n
\n
\n
2.2. Astrocytes and the effect of hyperammonemic conditions within CNS
\n
It is known that NH4+ and K+ have comparable physical and chemical properties, so that any change or increase in NH4+ concentrations may activate the Na+ transport by the Na+/K+-ATPase pump, leading to abnormal neurotransmission in neurons or even astrocytes [14]. NH4+ enters to the astrocytes and induces the increase in the activity of the GS; this event results in the accumulation of glutamine. As intracellular glutamine concentrations rise, the osmotic pressure does it in parallel, provoking the astrocytes to become swelling and to activate two main mechanisms to counteract this morphological change [15]. The first one consists of the release of an osmotic regulator, myoinositol; myoinositol leaves the astrocyte to redress the osmotic balance within the cell to prevent astrocyte and cerebral edema; while the other one is to increase the activity of the water channels called aquaporins (AQPs). One of the main water channel transporters related with regulation of the osmotic response in astrocytes, is the aquaporin 4 (AQP4) [16]. It has been reported that AQP4 increases its activity under hyperammonemic conditions, allowing the H2O molecules to enter into the cell, thus relieving the osmotic pressure induced by the accumulation of glutamine [17]. Until then, it was not clear whether the increased activity of AQP4 was the result of a higher transcriptional activity or an increased rate of mRNA translation [18]. Evidence in favor of both options had been reported. In two separate reports, Jalan et al. and Norenberg et al. demonstrated independently the increased expression of AQP4 protein, in a chronic or acute in vivo models of liver failure based on the bile duct ligation (BLD) or the use of thioacetamide (TAA) or acetaminophen (AAP), respectively [19, 20]. Accordingly, in vitro evidence indicates that ammonia-treated astrocytes also increase AQP4 protein levels [21]. On the other hand and in favor of transcription, additional evidence indicates that ammonium or mannitol, both osmotic stressors, increase the expression of AQP4 mRNA in vitro and in vivo, probably mediated by the p38-MAPK signaling pathway, which stimulates the tonicity-enhancer binding protein (TonEBP) to interact with the responsive enhancer element (TonE) over the AQP4 gene promoter region [17, 19, 22]. Further evidence indicates that other AQPs are direct targets of the hypothalamic arginine-vasopressin peptide (AVP) and the angiotensin II (ANGII) hormone; for instance, AVP controls the expression of AQP2 in the renal collecting duct cells under basal conditions, increasing the intracellular levels of cAMP that in turns modifies the activity of one of its targets, PKA; PKA phosphorylates the CREB protein allowing its translocation to the nucleus and its transcriptional activity [23]. It remains to be elucidated if AQP4 gene expression in hepatic encephalopathy conditions is also regulated by similar mechanisms.
\n
As we have seen, hepatic failure is closely related to astrocyte low grade and brain edema mediated by water movement throughout the AQP4 channel. Among the pathogenic factors contributing to aggravate this condition are the free radical production, the MAP-kinase activity, and the induction of the mitochondrial permeability transition (MPT) process. MPT is well known to occur in response to the sudden intra-cytoplasmic increase of molecules around 1.5 kDa in size that enters the mitochondria mediated by the so-called permeability transition pore (PTP), which is located at the inner membrane [24]. These phenomena critically compromises mitochondria homeostasis and the metabolic function of many crucial processes like the TCA and ATP synthesis, promoting the generation of reactive oxygen species (ROS). It seems that HE promotes the generation of ROS, therefore inducing the MPT due to the oxidative stress, because indirect evidence demonstrates that antioxidants are able to reduce MPT. Norenberg et al. demonstrated that MPT is involved in the ammonium-induced astrocyte swelling after their in vitro experiments based on the use of cyclosporine A (CsA), a well-known inhibitor of MPT [25]; in this study, the expression of the AQP4 protein was also inhibited by CsA, indicating a plausible crosstalk between different signaling pathways, such as the MAP-kinases or that conformed by the protein kinase A (PKA)/CREB, both of which might be related to the control of cell swelling in hyperammonemic conditions.
\n
\n
\n
2.3. Systemic and local inflammatory pathway effects on astrocyte disturbances
\n
Another important mechanism of regulation of astrocyte physiology in response to hepatic failure is the activation of the pro-inflammatory response. In recent years, an increasing role of the inflammatory-related pathways in response to ammonia-induced brain dysfunction has been reported. The cytokines promoting brain damage are TNFα, interlukin-6 (IL-6), interlukin1-beta (IL-1β), IL-18, and many others. However, there is controversy about the role between these pro-inflammatory cytokines in both acute and chronic hepatic failure. Several groups have provided evidence of a positive correlation in this interaction in human subjects or animal models. In 2007, Wright and colleagues determined the TNFα, IL-6, and IL-1β artery blood levels and found a positive correlation of these cytokines with intracranial pressure in ALF-affected humans [26]. Further evidence indicates that the same cytokines are elevated, at least at the transcriptional level, in the brains of a rat ALF model [27]. A recent interesting proposal about the role of these circulating inflammatory interleukins indicates that they might interact with certain blood-brain barrier (BBB) endothelial cells to reach the CNS, acting synergistically with ammonia. This synergistic model has been expanded through the identification of additional factors such as GABA produced by certain bacterial families within the gut, contributing to modify the GABAergic tone that reach the CNS via the vagal afferent pathway [28]. In view of these facts, systemic inflammation is in part responsible for the astrocyte and neuronal network alterations in both acute and chronic liver disease. A major player in the systemic inflammation effects over CNS in these pathologies is a member of the danger-associated molecular patterns (DAMPS) called high mobility group box protein 1 (HMGB1), which in basal conditions regulates transcriptional activity [29]; however, in pathological conditions, it can be released passively from damaged cells into the extracellular space in response to pro-inflammatory stimuli, such as LPS; HMGB1 can also be actively released by a JAK/STAT acetylation-mediated process, from immunocompetent cells [30]. In a recent study, Ohnishi et al. showed that HMGB1 significantly decrease the expression of AQP4 mRNA and protein in cultured astrocytes; conversely, the intra-cerebroventricular injection of HMGB1 in adult rats, slightly increase AQP4 protein expression and as expected, the brain edema; further, exposure of microglia to a HMGB had a significant effect over IL-1β mRNA expression and protein release, which apparently regulates AQP4 increased expression; the authors suggest that the pathway IL-1β-NF-κB-AQP4 in microglia might regulate the brain edema in response to HMGB1-mediated systemic inflammation [31]. Whether this pathway might occur with other pro-inflammatory cytokines such as TNFα, IL-6, or IFNγ, remains to be investigated.
\n
The unusual extracellular histone proteins represent another piece in the puzzle of the systemic inflammation response. It has been showed that in ALF or HBV infected patients, increased concentrations of circulating histones correlates with an immunostimulatory effect, leading to multiple organ injuries [32, 33, 34]. In vitro experiments with hepatic or monocyte cell lines stimulated with sera obtained from ALF patients, elicit cell death or release of inflammatory cytokines, respectively; interestingly, these effects were abolished with heparin—a histone-binding anticoagulant—suggesting that histone proteins are key players in the cellular injury and systemic inflammation observed in ALF-affected patients [32]. In addition to previously described consequences of the liver disease, including hyponatremia, sepsis, variceal bleeding, and renal failure; is the activation of microglial cells, the resident macrophages of the brain. Microglia increase the synthesis and release of inflammatory cytokines in a process called microgliosis [35]. Microgliosis is part of the most general response gliosis, which involves the astrocytes, the microglia, and oligodendrocyte cells; microgliosis is the local response to brain insults and typically represents the scar-promoting mechanism within the CNS.
\n
Along with systemic and local brain inflammation, the increased ammonia and manganese levels in the brain also alter the TCA cycle, promoting lactate accumulation and the promotion of dopaminergic cell death, as well as the generation of reactive oxygen species (ROS) in basal ganglia, and contributing in this way to the parkinsonism-like behavior and cognitive impairment observed in cirrhotic patients [36]. In this line of evidence, oxidative stress is thought to be of relevance for ammonia toxicity in HE. Molecular studies indicate that acute ammonia loading, mechanical or drugs stressors like hypo-osmolarity, diazepam, and TNFα, in vitro and in vivo, increases ribonucleic acid (RNA) oxidation. Among the oxidized RNA species, the 18 s rRNA and the glutamate/aspartate transporter (GLAST/SLC1A3) mRNA have been described; strikingly, the cerebral RNA oxidation in liver-injured rats predominates in the transport RNA granules located in close vicinity with postsynaptic spines, where learning and memory-associated protein synthesis occurs [37]. These data strongly suggest that ammonia-induced inflammation and RNA oxidation might impair both cognitive events in cirrhotic patients. In addition, it has been demonstrated that ammonia inhibits astrocyte proliferation promoting senescence both in vitro and in vivo, by means of the multidrug resistance-associated protein (Mrp) 4 and by a p38/MAPK-dependent activation of the cell cycle inhibitor genes GADD45α and p21 [38, 39].
\n
\n
\n
2.4. The role of the intestinal microbiota in the gut-liver-brain axis
\n
The intestinal microbiota has evolved as a new and relevant player in the pathogenesis of several intestinal and non-intestinal diseases. As the liver is the organ in closest contact with the intestinal tract, it is potentially exposed to bacterial components and metabolites. In physiological conditions, nutrients and bacterial compounds translocate to the liver via the portal circulation and contribute to the host homeostasis. As the epithelial wall and mucus layer act as physical barrier to impede that the most of the bacterial components or even bacteria reach the blood flow, it is usually accepted that a small quantity of these compounds enter the portal venous flow, and a tight balance on the immune response is achieved in order to fight against potential exogenous insults. However, in pathological conditions, such a physical barrier can become more permeable to bacterial components, specially lipopolysaccharide (LPS), flagellin, peptidoglycan, and microbial nucleic acids [40]. Evidence about the effect of gut microbiota over hepatic physiology has been demonstrated. In 2010, Gupta and co-workers found that small intestine bacterial overgrowth (SIBO) was a hallmark in cirrhotic patients suffering of HE [41]; in the same year, Jun et al. published evidence about the direct association of SIBO with the peripheral founding of bacterial DNA in cirrhotic patients [42]; later on, in 2012, Henao-Mejia et al. demonstrated that genetic deficiency of inflammasome, a protein complex considered the sensor of endogenous and exogenous pathogen-associated molecular patterns (PAMPS), induced the accumulation of bacterial components in the portal circulation, with the consequent liver damage effect [43]. One important fact about the bacterial overgrowth in cirrhotic patients is that the translocation of bacteria or any of its components promotes and aggravates the liver illness. There are several reports indicating the differences in the fecal microbiota of various populations around the globe, specifically in patients with liver cirrhosis in comparison with healthy subjects. In general, these studies coincides in founding that the phyla Proteobacteria and Fusobacteria, significantly increases in cirrhotic patients, compared with its healthy counterparts [44, 45, 46]; while at the genus level, the pathogenic Enterobacteriaceae, Alcaligenaceae, Porphyromonadaceae, Veillonellaceae, and Streptococcaceae families prevail and the beneficial taxa such as Lachnospiraceae and Bifidobacteriaceae, diminished in cirrhotic samples [45, 47]. In our laboratory, we conducted a pilot study in order to explore the changes in the microbiota of cirrhotic patients. Preliminary results indicate that some of these taxa previously reported are also present in the cirrhotic group of VHC-infected patients based in Mexico city; but we have also found that some other taxa have not been reported in other population (unpublished data); our findings are in concordance with the idea that additional variables, such as ethnicity or geographical location and even food ingestion habits, should be taken into account in order to interpret microbiome-derived studies, which eventually can be used in future clinical trials.
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Another significant consequence of SIBO is the higher tendency of the microbial community to increase the synthesis and release of organic compounds with a metabolic effect over a wide number of host cells. For example, it has been demonstrated that ingestion of L. rhamnosus, diminishes the expression of gamma-amino-butyric acid (GABA) receptor (GABAB) in the cingulate and prelimbic cortical regions of mice brain; this GABAB regulation implies a direct effect over neuronal physiology, which reflects in less anxiety and more antidepressant-like behavior in mice; moreover, vagotomised mice were unable to respond to L. rhamnosus, indicating that vagus nerve acts as an interface between gut bacteria and the brain [28]. Whether these bacteria produce a GABA-like neurotransmitter or directly modify the fire-threshold from vagus nerve remains a matter of study. Nowadays, molecular studies contributing to explain partially the mechanics behind the role of GABA and the intestinal microbiota have been published. Butterworth and colleagues in 1990 and 2008, found that brain samples from cirrhotic patients who died from HE, had unusual elevated levels of the peripheral-type benzodiazepine receptors (PTBZR) and of neurosteroids such as allopregnanolone (ALLO) or tetrahydrodeoxycorticosterone (THDOC) [48, 49]; interestingly, these neurosteroids are synthesized in the brain following activation of the translocator protein (TSPO), whose main activity is the cholesterol transport through the mitochondria, where stimulates the steroid biosynthesis [50]. Further evidence from Noremberg and co-workers indeed, indicates that astrocyte exposure to ammonia and manganese, significantly increase the TSPO activity, at least in vitro [51], indicating that neurosteroids are one of the main metabolites synthetized in response to hyperammonemic conditions as a result of dysbiosis and a lack of a functional urea cycle. However, there is some evidence indicating that some other metabolites produced by gut microbiota, such as the bile acids, tryptophan precursors, serotonin and catecholamine, might be able to signal through membrane receptors located in local cells of the gut epithelium or by a neurocrine or endocrine pathways; among these metabolites are the carbohydrate derivatives butyrate, acetate and propionate, which might be converted to short chain fatty acids (SCFAs); these SCFA in turn can reduce food intake and modulate the immune system response in the host [52, 53]. Different reports indicate that SCFAs are present in the enteroendocrine cells and on neurons of the submucosal and myenteric ganglia [54, 55]. Besides the SCFAs, it cannot be ruled out the possibility that some Gram-positive cell wall components are also capable of inducing neuronal or glial cell damage within the CNS of cirrhotic patients. In 2005, a report indicated that lipoteichoic acid (LTA) and muramyl dipeptide from Staphylococcus aureus induce a strong inflammatory response that ultimately lead to neuronal death by increasing nitric oxide (NO), superoxide (O2-), peroxynitrite (ONOO-), TNFα, IL-1β and IL-6, within astrocytes and microglia [56].
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Here, we can say that the net result of the so-called “dysbiosis” in cirrhotic patients is that a plethora of metabolic compounds like urea, methanol, short-chain fatty acids (SCFAs), and other volatile compounds are delivered or restricted to the host via the gastrointestinal tract. Altogether, these data indicate that intestinal bacteria play key roles in development and pathophysiology of hepatic liver over the CNS.
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2.5. Genetic and epigenetic effects induced by HE in astrocytes
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Epigenetic modifications are heritable and reversible stable marks that do not modify gene sequences per se, but have tremendous impact over the gene expression process. These marks allow the genome to adapt its transcriptional repertoire to different cellular and molecular conditions in response to environmental cues for fine-tuning of gene expression, and encompass a myriad of processes including histone, DNA and RNA modifications. One of the best-studied DNA modifications is the methylation (5-mC) and 5-hidroxy-methylation (5-hmC) of cytosine bases at the CpG dinucleotide sequence, mediated by the DNA methyltransferase (DNMT) or by the translocated in liposarcoma, Ewing’s sarcoma and TATA-binding protein-associated factor 15 (TET)-family of proteins, respectively [57]. It is widely accepted that the first mark, 5-mC, is a negative signal for gene expression to occur, while the 5-hydroxy-mC indicates the opposite. The role of DNA methylation dynamics within astrocytes is not yet known, at least in the context of HE derived from liver disease; however, specific data indicate that the NMDA receptor NR2B gene is negatively regulated by the neuron restrictive silencer factor (NRSF) in ethanol-exposed cortical neurons in vitro [58]; although specific analysis in this study indicates that NRSF directly interacts with the NR2B gene promoter region, there is no evidence of how ethanol regulates NRSF gene expression. Further evidence about the role of methylation or acetylation of glutamatergic or gabaergic-mediated signaling pathways affected by hyperammonemia remains to be elucidated.
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On the other hand, we know that non-coding RNAs (ncRNA) are important players in epigenetic mechanisms regulating cell fate and metabolism. Among the ncRNAs with relevant physiological roles are small RNAs and the long non-coding-RNAs (lncRNAs). A variant of small RNAs includes the microRNAS (miRNAs), which are beginning to acquire significant roles in coordinating astrocyte gene expression. miRNAs are small RNAs (~22 nt in length) that controls gene expression through their binding to the 3′-untranslated region (UTR) in mRNAs, leading transcripts to degradation or translational repression [59]. Long noncoding RNAs (lncRNA) on the other side are sequences of about 200 nt in length, which regulate the expression of neighbor protein-coding-genes in a phenomenon called “transvection” (for a systematic review see [60]). In the last decade, there has been an increase in the number of reports demonstrating the role of both miRNAs and lncRNAs in the physiopathology of HE. Two of the first reports regarding the role of two specific miRNA in the regulation of astrocyte cell swelling came from Singapore; in 2010 and 2012, Jeyaseelan and colleagues published in separate papers that miR-130a and miR-320a directly affect the AQP4 expression in the CNS. In the first case, the role of miR-130a is a non-canonical regulation, because the repression mechanism occurs at the transcriptional level over the AQP4 M1 gene promoter [61], while the mir320a was described as a modulator of AQP1 and AQP4 in a model of cerebral ischemia [62]. In a more wide recent study, Häussinger and co-workers explored the global miRNA profile using NH4Cl stimulated rat brain astrocytes in vitro. They were interested in the ammonia-dependent senescence observed in astrocytes and its relationship with miRNAs. By means of miRNA array experiments, they found that 43 of 336 miRNAs were significantly downregulated in hyperammonemic conditions, six of which (miR-31a-5p, miR-221-3p miR-221-5p, miR-222-3p, miR-326-3p, and miR-365-3p) seem to bind and regulate the mRNA encoding the heme oxygenase 1 (HO-1) protein; four of these miRNAs (miR-31a-5p, miR-221-3p, miR-222-3p, and miR-326-3p) were prevented to be downregulated by NH4Cl treatment, when astrocytes were exposed to the glutamine synthase inhibitor, methionine sulfoximine (MSO); moreover, the NADPH oxidase inhibitor, apocynin, fully prevented NH4Cl-mediated downregulation of the four miRNAs predicted to target HO-1, indicating that senescence is regulated by miRNA expression in cultured astrocytes and partly regulated by glutamine synthesis and NADPH-oxidase activity [63]. Data recently obtained in our laboratory indicate that three miRNAs (miR-29a-5p, miR-29b-3p, and miR-148b-3p) are repressed in brain tissue of a mouse model of liver cirrhosis. Interestingly, we found that the same miRNAs were downregulated in in vitro experiments using primary astrocytes incubated in the presence of NH4Cl (Figure 2); thus indicating that these miRNAs are strongly correlated with the physiological regulation of AQP4, both in basal and pathological conditions. Future experiments will allow us to demonstrate whether overexpression of these miRNAs by means of systemic or direct injection in hyperammonemic conditions counteracts the astrocyte cytotoxic edema.
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Figure 2.
The expression of miR-29 and miR-148 diminished in response to hyperammonemia in vivo and in vitro. Total RNA extracted from the whole brain of bile duct ligated (BDL) mice or control mice (Sham), as well as primary astrocytes (CD1) or the astrocytoma cell line T-98 in the presence or absence of NH4Cl, was used to evaluate the expression by means of qPCR. The data represent the mean expression of at least three replicates in each case (unpublished data).
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The lncRNAs, on the other hand, had been more less studied in the context of liver-associated CNS pathologies; however, in a recent study in which 35,923 lncRNAs were screened using microarrays, Silva and colleagues found that 380 and 486 transcripts were upregulated or downregulated in a mouse model of acute liver failure. The authors found that some of these lncRNAs might be related to the cytokine-receptor interaction, MAPK, insulin, NFκB, and TNFα signaling pathways, all of them related to the inflammatory response; the authors also found that the lncRNA uc007pjf.1 associated with a guanine nucleotide exchange factor (NET1), which regulates RhoA, is involved in the cytoskeleton dynamics, suggesting a relationship of this factor with the astrocyte cell swelling observed in HE [64]; these data are of relevance because contributes to corroborate the role of some genetic pathways already related with ALF and certainly established the roots to new discoveries; however, these findings are the result of a combination of cellular phenotypes within CNS and are hardly extrapolated solely to astrocytes, neurons, microglia or even to non-differentiated precursor cells residing in the frontal cortex; complementary in vitro or FACS-sorted cells experiments, should be carried out in order to acutely assign the contribution of each of these cell phenotypes to the physiopathology of liver disease.
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2.6. Clinical data in osmoregulation and systemic infections in cirrhotic patients with HE
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The maintenance of a constant cell volume is a critical problem of all cells. Cell swelling or shrinkage is undesirable for normal cellular function. Changes in the cell volume mostly occur due to changes in the extra or intracellular osmolarity. As most cell membranes are freely permeable to water and do not possess water pumps in their membranes, cells will shrink or swell in response to changes in the tonicity of the extracellular fluid (ECF) [65]. Cells will shrink in a hypertonic ECF, while they swell in a hypotonic ECF. Similarly, when the tonicity of the intracellular space of the cells increases, the cells try to compensate it and increase the osmolarity by the uptake of water from the ECF—and consequently swell. Extra- and intracellular osmolarity is determined by the concentrations of several compounds, such as ions, amino acids, etc. Consistent with the adaption against the rise of intracellular osmolarity in patients affected by CLF, it has been proposed that reductions in brain concentrations of myoinositol are implicated in the pathogenesis of ammonia-induced brain edema [66].
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In the same line of evidence, it is difficult to elucidate whether the release of taurine (an atypical aminoacid with osmoregulatory properties) from the astrocytes to the ECF is an osmoregulatory response to increased intracellular glutamine and/or cell swelling, since other mechanisms that increased intracellular osmolarity may lead to the cellular release of taurine and taurine may also be released from neurons. Taurine has been related with reversal of hepatic hypertension in a rat model of liver cirrhosis; in a study from 2009, Liang and colleagues found that natural taurine significantly decreased the portal venous pressure, resistance and flow, and markedly decrease the nitric oxide (NO) and cyclic guanine-monophosphate (cGMP), with a concomitant reduction in the pathological status of liver tissue damage and the expression of collagen 1 (COL-1), COL-III, and transforming growth factor-β1 (TGF-β1) [67]. Taurine also have clinical uses in the form of a hydrophilic bile acid called tauroursodeoxycholate (TUDCA) for treatment of primary biliary cirrhosis (PBC). In a randomized cross-over study with 12 female patients suffering from PBC, the use of TUDCA showed to improve the enrichment of biliary ursodeoxycholate (UDCA) and was better absorbed than ursodeoxycholate and undergoes less biotransformation than UDCA, thus suggesting that TUDCA is clinically relevant for the treatment of cholestatic liver diseases [68]. As taurine is synthetized in both liver and brain it is plausible that HE might impact on taurine metabolism and biological action. Several reports have indeed described the pathological disturbances in patients with chronic liver disease as well as in liver failure murine models. In both cases, the taurine concentrations were significantly diminished [69, 70]. Astrocytes synthetize and stored taurine, which is involved in ion movement across CNS, mainly K+ and Ca2+; therefore, is not rare to consider that neural excitability modifications in cirrhotic patients occurs. Evidence in favor of this hypothesis was reported in an experimental model of ALF, in which CSF taurine concentrations significantly increased in a positive correlation with early progression of HE [71]. As taurine has osmoregulatory actions any increase or decrease in its extracellular concentrations could have an impact in the pathogenesis of acute liver failure as has been demonstrated [72]. In contrast, taurine concentrations in chronic liver failure are not changed, but the release of taurine into the extracellular space could represent a control mechanism for volume regulation of astrocytes [73, 74].
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Another important metabolite that has been related with HE is the acidic calcium binding protein S100β, produced by astrocytes in the CNS and apparently secreted in response to oxidative stress, exerting its paracrine or autocrine effects on glia, neurons, and microglia [75, 76, 77]. S100β is a multifunctional protein that can be measured in basal conditions in CSF and is barely detected in circulating blood flow; however, in pathological conditions, its serum levels might increase, indicating neuronal or astrocytic damage. Our group and others have begun to investigate the diagnostic efficacy of S100β as a biomarker to detect low grade HE in cirrhotic patients. Recent findings from our laboratory indicate that cirrhotic subjects with OHE have higher serum levels of S100β when compared with non-HE cirrhotic or cirrhotic patients with MHE or control subjects, and that 0.13 ng/mL of S100β is the best cut-off for the diagnosis of HE (83 and 64% of sensitivity and specificity, respectively) [78]. These results are in accordance with previous data in which S100β and neuron-specific enolase (NSE) were evaluated in a small Egyptian cohort of 52 subjects, where 62 and 38% of 29 cirrhotic patients had HE grade 1 or 2, respectively; these groups were compared with non-HE cirrhotic or healthy subjects. Here, NSE showed non-significant differences among the groups, but S100β was increased in serum samples from grade 1 and 2 HE, compared with cirrhotic or healthy subjects; in addition, a significant positive correlation was found between S100β levels and plasma ammonia, in all patients; the main conclusion in this report was that S100β serum levels could be a useful surrogate marker with more than 90 and 50% of specificity and sensitivity, respectively, for detection of mild cognitive impairment in cirrhotic patients, before they progress to more advanced stages of HE [79]. In a similar study, Wiltfang et al. reported that a cut-off value of 112 pg./mL or 0.11 ng/mL of serum S100β, practically the same value found in our group of patients, is able to predict subclinical porto-systemic encephalopathy with a 100 and 57% of specificity and sensitivity, respectively [80].
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Osmotic abnormalities account for the cognitive impairment in cirrhotic patients and some clinicians are using the magnetic resonance (MR) in order to clearly demonstrate a relationship among water, manganese, glutamate, glutamine, and myoinositol levels and the degree of brain damage in patients with liver disease. MR might be useful to diagnose brain abnormalities elicited by hyperammonemia, especially in specific regions like the globus pallidum and the temporal region. It has been documented that N-acetylaspartate (NAA) is a good biomarker for neuronal loss and phosphocholine (Cho) concentrations reflects phospholipid metabolism and osmotic regulation due to its role in membrane synthesis and myelin destruction. Low levels of Cho have been associated with osmotic changes in the brain of cirrhotic patients. The majority of these metabolites have different echo times in MR spectroscopy with glutamate (Glu), glutamine (Gln), and phosphocreatine (PPC) being some of most constant correlation findings between patients with or without HE. However, in patients with OHE, the MR is difficult to perform because many confounding factors might co-exist, such as infection, renal failure, anemia, alcohol consumption, and other factors [81]. Our group recently conducted a pilot study in which non-infected compensated, infected cirrhotic, and healthy patients were evaluated to assess for cerebral changes in myoinositol and NAA by means of proton magnetic resonance spectroscopy (1H–MRs). Here, we have found that 40 and 30% of the infected patients were by spontaneous bacterial peritonitis or urinary tract infection, respectively; we also registered a significant decrease of myoinositol levels in the temporal region of non-infected cirrhotic and infected cirrhotic patients when compared with the healthy control group; in addition, we found a similar pattern whit NAA, which significantly diminished in the former groups (Figure 3) (unpublished data). When we sought over basal ganglia, Creatine, Cho as well as myoinositol levels did also significantly diminished in infected cirrhotic patients; altogether these results strongly suggests that acute infection in cirrhotic patients contributes to regulate brain metabolites and may be a factor related with development of HE (unpublished data).
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Figure 3.
Cirrhotic infected patients have significant abnormalities in the glutamine/glutamate (Glx) ratio and NAA brain levels. See text for details.
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Besides those data indicating that brain metabolites are also implicated in the pathophysiology of HE, another important issue in end-stage liver disease is the local blood flow. Cirrhotic patients with portal hypertension suffering ascites, hepatorenal syndrome and HE, usually also had distorted cerebral blood flow (CBF), which severely impact their skeletal muscle, brain, and kidney irrigation as a result of vascular resistance. It has been a long way since the 1960s decade, when one of the first studies about cerebral hemodynamics in cirrhosis came into light [82]. Since then, a plenty of studies have contributed to understand the role of vascular pressure over the pathology associated with HE. In 1969, Bianchi-Porro and co-workers reported that after portacaval shunt surgery, cirrhotic patients, had a significance increase in CBF and a significant decrease in cerebral vascular resistance (a measure of CBF and metabolism) and the metabolic rate of glucose and the glucose:oxygen quotient did also increase in these patients; the authors suggested that the increased CBF was related to metabolic problems, and that this increase accelerates the removal of toxic substances and allows the disposal of brain metabolites capable of neutralize toxic compounds [83]. It is now well accepted that cirrhotic patients have decreased CBF, portal hypertension, and splanchnic vasodilatation, associated with a hyperdynamic circulatory state, all of which can affect CBF. In a more recent study, we described a maneuver in which we used the transcranial Doppler (TCD) technique (transmission of ultrasound beam through the skull using a pulsed Doppler sectorial probe with a 2 MHz transducer), to measure in an non-invasive and reliable way, the cerebral autoregulation, meaning the physiological mechanisms that maintain CBF at an appropriate levels in response to vasoconstrictors or vasodilators and the middle cerebral artery (MCA) velocities. From here, two functional cerebral hemodynamic indexes were evaluated, (a) the pulsatility index (PI) which assesses the arteriolar vascular integrity and (b) the breath holding index (BHI), which measures cerebrovascular reactivity (CVR). We compared the TCD measures of cirrhotic non HE (n = 30), cirrhotic HE (n = 30) and healthy subjects (n = 30). Here, we found that major basal vessel integrity was not compromised because there were no differences among the three groups when the left and right cerebral arteries were evaluated. However, we observed significant differences in PI and BHI between cirrhotic and control subjects and when the compensated status was taken into account, the PI and BHI was significantly increased and decreased, respectively, when decompensated (CTP > 7 and MELD score ≥ 14) patients were compared with compensated and healthy groups. Similarly and more importantly, when HE status was included in the analysis, the results were the same as before, which means that disturbances in CBF is a novel pathophysiological pathway in HE, and opens an new way for treatment and prevention. Patients with decompensated cirrhosis or HE have a higher risk of cerebral hypoperfusion related with microvascular damage and the ability for autoregulation, which is and important feature for systemic blood pressure sudden changes, particularly hypotension, which can promotes HE [84]. These findings were similar to those reported by two separated groups, one located in Turkey, were 50 decompensated group of cirrhotic patients was compared with 50 healthy volunteers using the same TCD approach [85]; while other in China recruited a healthy control group (n = 40), a cirrhotic without HE group (n = 52), a cirrhotic with MHE group (n = 21) and a cirrhotic with OHE group (n = 19) [86]. Here, in the first case, the authors analyzed the spectra signal derived from the systolic velocity, diastolic velocity, mean flow velocity (MFV in cm/s), pulsatility, and the resistive indexes (PI = Peak systolic velocity (Vp) – end-diastolic velocity (Vd)/MVF; and RI = Vp − Vd/Vd) of intracranial arteries. Patients with cirrhosis had a lower MFV compared to control healthy group, while cirrhotic patients had a higher PI and RI values and a positive correlation exists with the model for end-stage liver disease (MELD) score and the RI values of patients with ascites, which were higher than those without ascites [85]. In the second case, authors found that mean velocity (Vm), Vd, PI, and RI, as well as the serum ammonia levels, were decreased in the group of cirrhotic patients with MHE subject to lactulose treatment, when compared with the placebo group, while a positive correlation was found between ammonia and PI, RI, cognitive test results and Vd; authors propose that cerebral hemodynamics is related with the severity of HE and that lactulose treatment is able to significantly improve this parameter in cirrhotic patients [86].
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3. Novel pharmacological findings over HE treatment
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Despite being one of the most frequent and best studied associated pathologies of liver dysfunction, HE still represents a bigger challenge to clinicians due to its devastating effects over cognitive functions. Still, there is no clear consensus about its appropriate treatment because of its complex physiology involving inflammatory responses, neurosteroid-like compounds, reactive oxygen species, etc. In addition, there is another layer of complexity represented by the co-infections and organ failure that many patients develop in the course of the pathology. Nowadays, there had been a lot of attempts to circumvent the signs and symptoms of HE, both experimentally and clinically. One example of this is the use of one of the most popular anti-inflammatory drugs used to treat cirrhotic patients, infliximab, which reduces peripheral inflammation, directly impacts over neuroinflammation, and restores the altered neurotransmission and cognitive impairment, as well as the reversal of activation of microglia and astrocyte GABA transporters (GAT1, GAT3). Infliximab also reduces the synthesis and release of pro-inflammatory cytokines, such as TNFα, IL-1β, etc., as demonstrated by Dadsetan et al. in a murine model of HE [87, 88]. These data are still scarce in human subjects, although some advance have been reported. In an initial trial, Sharma and co-workers reported that patients with severe alcohol-associated hepatitis, who received a single dose of infliximab (5 mg/kg IV), have an improvement of the Maddrey’s discriminant factor (DF)—useful in the prediction of short-term prognosis—serum TNFα, C reactive protein (CRP), MELD score and total neutrophil count compared with the before-treatment parameters; interestingly, among the patients who survived only 8% had HE at admission, while among those who died, 67% suffer from HE; the authors concluded that HE at admission of the trial, Lille score and delta bilirubin, predicted 2-month mortality and that infliximab should be carefully used to treat alcoholic hepatitis [89]. Besides the use of infliximab, other therapies aimed to reduce the production of ammonia by the intestinal microbiota, especially the coliforms, have been widely reported. Treatment with lactulose (a non-absorbable disaccharide) or non-absorbable antibiotic rifaximin, are two of the most frequent therapies for cirrhotic patients suffering from HE. The metabolic activity of colonic bacteria which produce short-chain organic acids when metabolize lactulose lowering the pH of the gastrointestinal tract, is the main effect of the disaccharide for the removal of nitrogen; the acidic environment also results in the change of ammonia to ammonium (NH4+) a non-absorbable form of nitrogen which diminishes the circulating ammonia. Further mechanisms include the laxative effect for removal of nitrogen-containing compounds from the gut. In a concise Cochrane review from last year, 38 clinical trials were evaluated and their findings indicate that non-absorbable disaccharides have beneficial effects when compared with placebo/no intervention on mortality, HE, liver failure, hepatorenal syndrome and variceal bleeding; secondary outcomes such as quality of life, also were favored when non-absorbable disaccharides were administered [90]. Additionally, experimental data indicates that lactulose promotes neuro- and astrogenesis in the hippocampus of rats with HE as well as the reduction of plasma ammonia, the locomotor activity impairment and neuronal hyperactivity in brain areas related with locomotor activity [91]. These data are in accordance with those data indicating that Lactulose do also improved cognitive function in MHE patients, as reviewed by Luo et al. [92]. The non-absorbable antibiotic, rifaximin, is the most common additive therapy along with lactulose to treat cirrhotic patients with HE. In a recent prospective observational study, 60 HE patients were divided into two groups, one receiving rifaximin alone and the other one received rifaximin plus lactulose for 7–15 days until discharge from hospital or death. In this study, the authors found that both groups were effectively improved in their mental scores, although they conclude that the combination of both substances was effective, but not superior to lactulose alone in the treatment of HE [93]. The resolution of overt HE has also been tested using rifaximin in comparison with other antibiotics. A meta-analysis of these trials indicates that rifaximin treatment was more likely to resolve an episode in patients with OHE besides an improvement in secondary prevention of HE [94]. Other treatment regimes devoted to reduce the serum ammonia levels, such as polyethylene glycol (PEG), sodium benzoate, odium phenylacetate, glycerol-phenylbutyrate (GPB), ornithine-phenylacetate (OP), phenyl-acetyl-glutamine (PAGN), and a carbon microsphere adsorbent (AST-120) among others, had been also tested for nitrogen removal (for a concise review see [95]).
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On the other hand, it is more common to see the rise of many biological compounds that previously were used to treat distinct pathologies; an example of this is Artesunate, a water-soluble hemisuccinate derivative of the Chinese herb Artemisia annua, that has been recommended for its use as an antimalarial drug, but it seems that also have anti-inflammatory properties because its use in cancerous cells inhibits its replication and interferes with the expression of pro-inflammatory genes [96, 97]. Artesunate do also have anti-profibrotic properties as was demonstrated recently by Wang and colleagues. Here, Wang et al. investigate the role of treatment with artesunate in a lung fibrosis rodent model; the authors found that artesunate treatment successfully reverted the expression of pro-fibrotic genes such as transforming growth factor (TGFβ), Smad3, and α-smooth muscle actin (α-SMA) as well as the heat shock protein 47 (HSP47) at the protein level, when compared with control animals [98]; these results are in accordance with those of Wang et al., whose findings in the RLE-6TN cell line indicates that TGFβ and Smad3 are inhibited after artesunate exposure [99]. The effect of artesunate on the CNS of rats with HE has been tested too. Rats administered with artesunate (50 or 100 mg/kg), significantly improved its spatial learning ability in the Morris water maze test, while in vitro, cerebellar granule neurons treated with artesunate (100 μM) significantly reduced its glutamate release, as well as the Na+K+-ATPase activity, indicating that artesunate has a neuroprotective effect, although the effect over astrocytes was not evaluated in this work [100]. Additional evidence about the effect of artesunate over glial cells is lacking, but this drug has a relevant role in the field of the HE treatment choices. A synthetic drug called GR3027 has been tested in vivo in a rat model of HE. This new compound has antagonist properties over the GABAA receptors when subcutaneously administered and effectively reverses the motor coordination and spatial memory impairment in rats with experimental HE, offering a new way to prevent the ammonia-induced neurological GABA-related damage [101]. These findings are similar to those reported by Turkmen et al. using the UC1011 GABAA receptor antagonist, who also observed a reduced allopregnanolone effect on the learning test [102].
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Although the mechanisms of astrocyte cell swelling are still controversial, some authors propose that the plasma membrane depolarization plays a crucial role, while others suggest that the ionic homeostasis is equally important [103, 104]. In addition, glutamine, manganese, pH changes, and the neurosteroids are also implicated in this process. However, both, in vivo and in vitro experimental evidence strongly suggests that astrocyte swelling is the primary response to hyperammonemia. One additional factor is the oxidative stress derived from the altered mitochondria. It has been shown that astrocytes exposed to ammonia, results in the activation of the mitochondrial permeability transition pore (MPT), a process related to generation of ROS within the cell. The permeability transition is a sudden increase in the inner mitochondrial membrane to solutes >1.5 kDa and it is known that adenine nucleotides inhibit this process. The MPT is a Ca2+-dependent process that usually culminates in necrosis or apoptosis in hepatocytes; in mammals, cyclophilin D (CyPD) (a conserved cis-trans isomerase) acts as the mitochondrial receptor for cyclosporine A (CsA) (a very well-known immunosuppressive agent). The MTP is a multiprotein complex whose formation is ultimately inhibited by the CyPD/CsA complex. Pre-treatment of astrocytes with CsA completely reverts the cell swelling after treatment with ammonia [25]; in a similar manner, sodium pyruvate, minocycline, magnesium sulfate, and trifluoparazine (TFP), decreased the ammonia-induced MTP-dependent cell swelling, in a significant manner [105]. Other antioxidant compounds have been tested in order to revert the cognitive impairment in HE. For example, the multifunctional soy isoflavone, genistein, has an important activity as an oxygen-derived free radicals scavenger, and as a potent inhibitor of pro-inflammatory cytokines such as IL-4, IL-10, IL-1β, TNFα, etc., as well as the expression of GABAA and GluR2 receptors in the hippocampus of a rat model of HE, restoring the altered neurotransmission, neuroinflammation and the DNA damage observed in the rat’s brain [106, 107]. Further evidence indicates that genistein may inhibit astrocyte swelling by inhibiting the protein tyrosine kinase (PTK) activity and repression of NF-κB-mediated inducible nitric oxide synthase (iNOS)-derived nitric oxide (NO) accumulation [108]. Resveratrol, lipoic acid (LA), and N-acetyl-cysteine (NAC) are important anti-oxidants that can, at least in vitro, modulate the expression and activity of the glutamate transporters, increase the glutamate release, reduce the activity of GS and GSH content as well as the ammonia-induced pro-inflammatory response in glial cells [109].
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A most recent study, conducted in vivo, indicates that TNFα and its receptors, TNFR1 and TNFR2, play major roles in acute ammonia intoxication. In TNFα-deficient or double TNFR1/TNFR2 knock-out mice, ammonia challenge is unable to trigger astrocyte cell swelling, an affect that seems to be related to the expression of the Na+, K+, 2Cl− (NKCCl) co-transporter, which is closely related to the NH4+ hepatic clearance [110].
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L-ornithine and L-aspartate (LOLA) are urea cycle substrates that can lower ammonia levels in cirrhotic patients. The first is a substrate of the ornithine-aminotransferase (OAT) enzyme, which converts ornithine into glutamate or glutamate-semialdehyde, while L-aspartate is converted by the aspartate-aminotransferase into glutamate or oxaloacetate [5]. A complete review about the effect of LOLA in cirrhotic patients has been published and one of the main conclusions was that LOLA is effective in patients with OHE and less beneficial for those having MHE and had no effects on patients with acute liver failure [111, 112].
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An intriguing method to treat liver-affected patients is based in Ayurveda. According to Wikipedia, Ayurveda is a system of medicine with roots in India, where medical knowledge is transmitted from gods to sages and then to humans. Ayurveda therapies are based on complex herbal compounds, minerals, and metal substances. In a clinical research paper, Ayurveda was put into practice to treat a case of HE in India. The report indicates that Ayurvedic therapy, consisting on a mix of four substances (Siddha Makar Dhwaja, Brihat Vata Chintamani Rasa, Phyllanthus niruri extract and a syrup of “hepatoprotective herbs”), was administered to a grade three HE male patient currently receiving “modern therapies.” After a 3-day period of treatment, the patient was found more oriented and awake. The hepatic aminotransferases and bilirubin significantly improved after almost 1 month of treatment [113]. This report, according to authors, is interesting enough to begin a new debate in the area of practice of Ayurvedic medicine. The debate is open.
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4. Concluding remarks
\n
Hepatic encephalopathy is a very devastating disease associated with liver failure. Besides the detrimental effects over astrocyte and neuron physiology, HE had a direct impact over the quality of life of affected patients. Recent evidence suggests that many pro-inflammatory pathways are related to these pathology and therapeutic interventions are devoted to counteract it. In this chapter, many of the molecular and pathological events related with ammonia and its effects over astrocytes cells had been addressed. Indeed, ammonia is one of the main factors contributing to the pathophysiology of HE, responsible of the astrocyte swelling along with other metabolites such as myoinositol, manganese, etc. (Figure 4). Ammonia is a toxic compound mainly produced by the bacteria in the gastrointestinal tract or by metabolism of ammonium-containing substances. In healthy subjects, urea is the final metabolite of ammonium metabolism in the liver, which is then excreted in urine. Hepatic failure is a one of the most common public concerns in western economies and is beginning to become a major problem in the next 10–15 years. Some of the most feasible and easy-to-implement therapies against liver disease is prevention. Public health policies must be strengthened regarding preventive information not only for liver but also to different metabolic-related illness. The stress and inappropriate feeding habits in general population has enormous impact not only in adults, but also in young or even in elementary-school grade childhood. One of the main tasks of public health should be informative and not only the medical practice. If we want to succeed in our struggle against different maladies affecting human beings, we must to begin to turn the sight to the basics of having a proper balanced diet and to make regular physical activity; this actions would improve and prevent any metabolic imbalance in the short to median term. The society has the future in their hands.
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Figure 4.
Proposed model of astrocyte dynamic during hyperammonemic conditions. Here, the ammonia (triangle) molecules are increased in the extracellular space and they easily diffuse through the plasma membrane or by means of the NKCC1 channels (dark gray cylinders) once inside ammonia is conjugated with glutamate (Glu) by the enzyme glutamine synthase (not shown) to generate glutamine (Gln). This is the GGC previously described (see Figure 1). In hyperammonemic conditions, such as that resulting from liver cirrhosis, the amount of Gln exceeds the astrocyte capacity to export it. Then, astrocyte increase the expression of the water channel AQP4 (light gray cylinders) in order to let water (snow flake-like spots) to get inwards. These process is accompanied by the increase of different interleukines like TNFα, IL-1β, IFNγ, and other pro-inflammatory cytokines (IL´s), which promotes the mitochondria to become less effective in its metabolic functions, leading the astrocyte to an stressed state. This process generates reactive oxygen species (ROS) and reactive nitrosative species (RNS), as well as oxidized RNAs (short lines) that eventually impairs the astrocyte overall function. The whole process generates a condition of low-grade cellular edema and astrocyte cell swelling. See text for additional details: (NH4+), (Glu), (Gln), (dark gray cilinders), (light gray cylinders), (snow flake-like spots).
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\n\n',keywords:"liver, hyperammonemia, encephalopathy, astrocytes, astrogliosis",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/58516.pdf",chapterXML:"https://mts.intechopen.com/source/xml/58516.xml",downloadPdfUrl:"/chapter/pdf-download/58516",previewPdfUrl:"/chapter/pdf-preview/58516",totalDownloads:1183,totalViews:362,totalCrossrefCites:0,totalDimensionsCites:0,totalAltmetricsMentions:0,impactScore:0,impactScorePercentile:12,impactScoreQuartile:1,hasAltmetrics:0,dateSubmitted:"May 16th 2017",dateReviewed:"November 15th 2017",datePrePublished:"December 20th 2017",datePublished:"March 21st 2018",dateFinished:"December 30th 2017",readingETA:"0",abstract:"Liver disease is one of the major chronic disabilities around the world. It is known that global casualties are increasing because of virus C infection, alcohol consumption, or non-alcoholic circumstances. One of the main derived comorbidities of liver disease is the hepatic encephalopathy (HE), a severe neuropsychological syndrome derived from the acute or chronic liver disease. A key feature accounting for HE symptoms in cirrhotic patients is brain edema, which is triggered by hyperammonemia. In basal conditions, ammonia can be metabolized in the central nervous system (CNS) by astrocytes, which synthetize glutamine using ammonia and glutamate as substrates. In hyperammonemic conditions, astrocytes synthetize large amounts of glutamine generating a hyperosmotic condition, inducing these cells to become swollen in shape, invoking the characteristic symptom clinically manifested in patients with HE, as brain edema; this condition is regulated by water channels called aquaporins (AQPs) and by other molecules such as myoinositol. Experimental evidence suggests that some small non-coding RNAs may regulate AQPs expression both in vivo an in vitro and that some pharmacological interventions improve cognitive impairment in cirrhotic patients. It is undeniable that astrocytes and the different signaling pathways beneath its plasma membrane play a crucial role in liver disease-derived HE and represent some of the novel pharmacological targets to treat comorbidities of the liver disease.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/58516",risUrl:"/chapter/ris/58516",book:{id:"6271",slug:"astrocyte-physiology-and-pathology"},signatures:"Carlos Pérez-Monter and Aldo Torre-Delgadillo",authors:[{id:"211176",title:"Prof.",name:"Carlos",middleName:null,surname:"Pérez-Monter",fullName:"Carlos Pérez-Monter",slug:"carlos-perez-monter",email:"carlos.perezm@incmnsz.mx",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Instituto Nacional de Ciencias Médicas y Nutrición Salvador Zubirán",institutionURL:null,country:{name:"Mexico"}}},{id:"211276",title:"Dr.",name:"Aldo",middleName:null,surname:"Torre-Delgadillo",fullName:"Aldo Torre-Delgadillo",slug:"aldo-torre-delgadillo",email:"detoal@yahoo.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_1_2",title:"1.1. General aspects of liver disease and hepatic encephalopathy",level:"2"},{id:"sec_3",title:"2. Astrocytes as mediators of the pathophysiology of HE",level:"1"},{id:"sec_3_2",title:"2.1. Ammonium metabolism",level:"2"},{id:"sec_4_2",title:"2.2. Astrocytes and the effect of hyperammonemic conditions within CNS",level:"2"},{id:"sec_5_2",title:"2.3. Systemic and local inflammatory pathway effects on astrocyte disturbances",level:"2"},{id:"sec_6_2",title:"2.4. The role of the intestinal microbiota in the gut-liver-brain axis",level:"2"},{id:"sec_7_2",title:"2.5. Genetic and epigenetic effects induced by HE in astrocytes",level:"2"},{id:"sec_8_2",title:"2.6. Clinical data in osmoregulation and systemic infections in cirrhotic patients with HE",level:"2"},{id:"sec_10",title:"3. Novel pharmacological findings over HE treatment",level:"1"},{id:"sec_11",title:"4. 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Lactulose enhances neuroplasticity to improve cognitive function in early hepatic encephalopathy. Neural Regeneration Research. 2015;10(9):1457-1462\n'},{id:"B92",body:'Luo M, Li L, Lu CZ, Cao WK. Clinical efficacy and safety of lactulose for minimal hepatic encephalopathy: A meta-analysis. European Journal of Gastroenterology & Hepatology. 2011;23(12):1250-1257\n'},{id:"B93",body:'Ahire K, Sonawale A. Comparison of Rifaximin plus lactulose with the lactulose alone for the treatment of hepatic encephalopathy. The Journal of the Association of Physicians of India. 2017;65(8):42-46\n'},{id:"B94",body:'Kimer N, Krag A, Moller S, Bendtsen F, Gluud LL. Systematic review with meta-analysis: The effects of rifaximin in hepatic encephalopathy. Alimentary Pharmacology & Therapeutics. 2014;40(2):123-132\n'},{id:"B95",body:'Rahimi RS, Rockey DC. Novel ammonia-lowering agents for hepatic encephalopathy. Clinics in Liver Disease. 2015;19(3):539-549\n'},{id:"B96",body:'Karpel-Massler G, Westhoff MA, Kast RE, Dwucet A, Nonnenmacher L, Wirtz CR, Debatin KM, Halatsch ME. Artesunate enhances the antiproliferative effect of temozolomide on U87MG and A172 glioblastoma cell lines. Anti-Cancer Agents in Medicinal Chemistry. 2014;14(2):313-318\n'},{id:"B97",body:'Xu H, He Y, Yang X, Liang L, Zhan Z, Ye Y, Yang X, Lian F, Sun L. Anti-malarial agent artesunate inhibits TNF-alpha-induced production of proinflammatory cytokines via inhibition of NF-kappaB and PI3 kinase/Akt signal pathway in human rheumatoid arthritis fibroblast-like synoviocytes. Rheumatology. 2007;46(6):920-926\n'},{id:"B98",body:'Wang C, Xuan X, Yao W, Huang G, Jin J. Anti-profibrotic effects of artesunate on bleomycin-induced pulmonary fibrosis in Sprague Dawley rats. Molecular Medicine Reports. 2015;12(1):1291-1297\n'},{id:"B99",body:'Wang CM, Chen J, Jiang M, Xuan XP, Li HX. Relationship between artesunate influence on the process of TGF-beta1 induced alveolar epithelial cells transform into mesenchymal cells and on idiopathic pulmonary fibrosis. Yao xue xue bao = Acta pharmaceutica Sinica. 2014;49(1):142-147\n'},{id:"B100",body:'Wu YB, Zhang L, Li WT, Yang Y, Zhao JM. Artesunate restores spatial learning of rats with hepatic encephalopathy by inhibiting ammonia-induced oxidative damage in neurons and dysfunction of glutamate signaling in astroglial cells. Biomedicine & Pharmacotherapy = Biomedecine & Pharmacotherapie. 2016;84:972-978\n'},{id:"B101",body:'Johansson M, Agusti A, Llansola M, Montoliu C, Stromberg J, Malinina E, Ragagnin G, Doverskog M, Backstrom T, Felipo V. GR3027 antagonizes GABAA receptor-potentiating neurosteroids and restores spatial learning and motor coordination in rats with chronic hyperammonemia and hepatic encephalopathy. American Journal of Physiology Gastrointestinal and Liver Physiology. 2015;309(5):G400-G409\n'},{id:"B102",body:'Turkmen S, Lundgren P, Birzniece V, Zingmark E, Backstrom T, Johansson IM. 3beta-20beta-dihydroxy-5alpha-pregnane (UC1011) antagonism of the GABA potentiation and the learning impairment induced in rats by allopregnanolone. The European Journal of Neuroscience. 2004;20(6):1604-1612\n'},{id:"B103",body:'Allert N, Koller H, Siebler M. Ammonia-induced depolarization of cultured rat cortical astrocytes. Brain Research. 1998;782(1-2):261-270\n'},{id:"B104",body:'Norenberg MD. Astrocytes and ammonia in hepatic encephalopathy. In: Vellis JD, editor. Neuroglia in the Aging Brain. 1st ed. Vol. XIII. New York: Springer Science + Business Media, Humana Press; 2002. p. 513\n'},{id:"B105",body:'Reddy PV, Rama Rao KV, Norenberg MD. Inhibitors of the mitochondrial permeability transition reduce ammonia-induced cell swelling in cultured astrocytes. Journal of Neuroscience Research. 2009;87(12):2677-2685\n'},{id:"B106",body:'Ganai AA, Husain M. Genistein alleviates neuroinflammation and restores cognitive function in rat model of hepatic encephalopathy: Underlying mechanisms. Molecular Neurobiology. 2017\n'},{id:"B107",body:'Ganai AA, Husain M. Genistein attenuates D-GalN induced liver fibrosis/chronic liver damage in rats by blocking the TGF-beta/Smad signaling pathways. Chemico-Biological Interactions. 2017;261:80-85\n'},{id:"B108",body:'Dai H, Jia G, Wang W, Liang C, Han S, Chu M, Mei X. Genistein inhibited ammonia induced astrocyte swelling by inhibiting NF-kappaB activation-mediated nitric oxide formation. Metabolic Brain Disease. 2017;32(3):841-848\n'},{id:"B109",body:'Bobermin LD, Hansel G, Scherer EB, Wyse AT, Souza DO, Quincozes-Santos A, Goncalves CA. Ammonia impairs glutamatergic communication in astroglial cells: Protective role of resveratrol. Toxicology In Vitro: An International Journal Published in Association with BIBRA. 2015;29(8):2022-2029\n'},{id:"B110",body:'Pozdeev VI, Lang E, Gorg B, Bidmon HJ, Shinde PV, Kircheis G, Herebian D, Pfeffer K, Lang F, Haussinger D, et al. TNFalpha induced up-regulation of Na+, K+, 2Cl− cotransporter NKCC1 in hepatic ammonia clearance and cerebral ammonia toxicity. Scientific Reports. 2017;7(1):7938\n'},{id:"B111",body:'Acharya SK, Bhatia V, Sreenivas V, Khanal S, Panda SK. Efficacy of L-ornithine L-aspartate in acute liver failure: A double-blind, randomized, placebo-controlled study. Gastroenterology. 2009;136(7):2159-2168\n'},{id:"B112",body:'Jiang Q, Jiang XH, Zheng MH, Chen YP. L-ornithine-l-aspartate in the management of hepatic encephalopathy: A meta-analysis. Journal of Gastroenterology and Hepatology. 2009;24(1):9-14\n'},{id:"B113",body:'Rastogi S, Srivastav PS. Ayurveda in critical care: Illustrating Ayurvedic intervention in a case of hepatic encephalopathy. Ayu. 2011;32(3):345-348\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Carlos Pérez-Monter",address:"carlos.perezm@incmnsz.mx",affiliation:'
Department of Gastroenterology, National Institute of Medical Sciences, Salvador Zubiran, Mexico
Faculty of Medicine, National University of Mexico, Mexico
Department of Gastroenterology, National Institute of Medical Sciences, Salvador Zubiran, Mexico
Faculty of Medicine, National University of Mexico, Mexico
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1. Introduction
Issues generated from changing climate are trending throughout the globe and have altered various Earth ecosystem processes [1]. Climatic variability assumes about 60% of yield variability, and therefore, it is considered a critical factor to influence crop productivity and farmer’s income. In addition to crop yield and productivity, different natural resources such as land and water are also exploited and have a crucial impact on agricultural production [2]. The primary reason for the substantial changes in climate in the last few decades is the excessive anthropogenic activities that transformed the composition of the global atmosphere. Since 1750, the greenhouses gases (GHGs) concentration increased, including methane (150%), carbon dioxide (40%), and nitrous oxide (20%), respectively [3].
The growing population has increased the demand for food that has resulted in intensive agricultural practices such as excessive fertilizer usage, manipulation of water resources, and livestock generation. Furthermore, such agricultural activities result in producing GHGs, thus polluting natural resources. Additionally, climate change adversely degrades the land resulting in increased desertification and having nutrient-deficient soils. The threat of growing land degradation day by day is another issue observed worldwide. Global Assessment of Land Degradation and Improvement (GLADA) reported that a quarter of the global land has not to be categorized as degraded. Climate change and anthropogenic activities are the key factors to deteriorate the 15 billion tons of fertile soil every year, and its 1.5 billion people are also affected [1].
The agriculture sector is also prone to climate change as it is sensitive to weather conditions and causes massive impacts on economics. The crop yield is also affected by changes in climatic events, including temperature and rainfall. Increase in temperature, changes in precipitation patterns, and CO2 fertilization vary due to the crop, location, and magnitude of change in the parameters (Figure 1). The increase in precipitation is likely to reduce the temperature, which ultimately reduces the crop yield. Moreover, humidity and wind speed also impact crop productivity and insect pests and diseases, which are more active in humid and warmer conditions [3]. Climate change has also contributed to drought, increasing sea levels, intense storms, and floods, resulting in land degradation [4].
Figure 1.
Environmental impacts resulting from climate change.
A collection of small molecules having a different structure that contributes to improving various plant growth and development processes and showing significant results against biotic and abiotic stresses are termed as plant hormones. Moreover, plant hormones regulate different mechanisms such as seed germination, cell differentiation, cell proliferation, senescence, stem elongation, organ formation and response to drought, pest attack, and wounding. Thus, plant growth and productivity, size, and architecture are controlled by plant hormones. In addition, it can be a possible solution to improve agricultural productivity and solve the worldwide food storage issues [5, 6].
Plant hormones can also be defined as the plant growth regulators either produced inside or by the plants, whereas plant growth regulators are synthetic materials that can alter plant biological processes and improve its growth [6, 7]. Major classical hormones included in the plant growth regulator category are abscisic acid, cytokinin, ethylene, auxin, jasmonate, gibberellin, salicylic acid, brassinosteroids—however, many more there to be discovered. For the last few years, the understanding of the plant hormones and their association with various plant processes, the mechanism behind them, and their signaling roles has been progressed [8].
In this chapter, we have aimed to understand plant hormones as a tool to achieve agricultural sustainability to tackle climate change. The chapter consists of eight sections, which describes the introduction (Section 1), interaction of plant hormones and plant physiology (Section 2), role of plant hormones in adaptation to salt stress (Section 3), participation of plant hormones in heat and cold stress tolerance (Section 4), the response of plant hormones to drought stress (Section 5), the involvement of phytohormones in resetting plant-pest interaction (Section 6), future prospects and challenges (Section 7), and the conclusion (Section 8), respectively.
2. Interaction of plant hormones with plant physiology
Plant hormones are chemicals and should not be considered nutrients. These hormones are programmed to respond at a specific time or growth stage, or cycle. However, before or after that specific stage, the impact of hormones will diminish [9]. Due to climate change, plants face various biotic and abiotic stresses, including salinity, cold and heat stress, drought, insects, and pathogens attack that adversely impact plant growth and yield. However, plant hormones in a small amount not only protect the plant from environmental stresses but also improve crop yield [10], as described in Table 1.
Plant hormone
Identified primary function
References
Abscisic acid
Impacts various cellular processes (i.e.,) seed maturation and germination, stomatal movement, and leaf senescence.
Pivotal roles of plant hormones in plant growth and development.
Plant hormones help to attain resistance in plants against induced stress (Figure 2). Abscisic acid is related to the plant stress responses such as cold, drought, salinity, and plant growth, including seed dormancy, embryo maturation, flower induction, and pest attack [18]. Cytokinin is a hormone produced by plants as well as nearby insects and pathogens. However, it induces defense mechanisms in plants upon pathogen attack and impacts the plant physiological traits, including apical dominance, seed germination, leaf senescence, flower, and fruit development, whereas type of molecules of cytokinin hormones varies depending upon the plant growth stages and environmental conditions [19].
Figure 2.
Plant hormones enable the plants to sustain against environmental stresses.
Ethylene has a significant role in leaf growth, development, senescence. However, the response depends on the concentration of hormones and the plant species. Therefore, the effect of ethylene on plant physiology might be an independent response or dependent on the interaction with other hormones. Moreover, ethylene has been shown to play an antagonistic role to auxins in the abscission of various organs. Furthermore, ethylene is vital for fruit ripening, plant aging, and protecting the seed until maturity [13]. On the other hand, auxin is a growth hormone and involves in plant growth and development through cell elongation and expansion. It also regulates organ development, shoot, root branching, gravitropism, and phototropism [20].
Jasmonic acid is a plant hormone and is involved in plant defense mechanisms. Thus, the plant can perform effectively under stressful environmental conditions. Its interaction with ethylene improves root development and anthocyanin accumulation that could be related to its tolerance against abiotic stresses [10]. Furthermore, it is involved in the inhibition of seed germination. The mechanism behind the role of Jasmonic acid varies depending upon the environmental constraints [21]. Gibberellin is required by the plants at multiple stages and contributes to germination, the transition to flowering, and flower development, root elongation, and fruit development [22].
Salicylic acid is also a defense-boosting hormone as its level increases with pest attack [21]. In addition, brassinosteroids regulate specific gene sets to help plants sustain during unfavorable environmental conditions [23]. Moreover, it is also involved in various metabolic processes, including osmotic regulation, plant-water interaction, photosynthesis, nitrogen metabolism, and antioxidant metabolism [24].
3. Role of plant hormone in adaptation to salt stress
With the increasing population, it is challenging to fulfill the food requirements, as climate change has threatened the sustainability and productivity of the agriculture production system [25]. Different types of abiotic stresses are present in nature, affecting the various processes in plants and indicating the unique and complex response against the stresses, depending on multiple factors such as degree of plasticity, including many morpho-physiological, cellular, and anatomical [26]. According to an estimate, about 6% of the world’s total land area is affected by salinity. Among various biotic and abiotic stresses, salinity also plays a vital role in decreasing crop growth and productivity [27] that has been intensified due to poor irrigation practices, increasing population, and industrial pollution [28]. Some other types of stress, including osmotic stress, ionic stress, and oxidative stress, occur in the plant because of salt stress. Consequently, to survive under such conditions, plants need to rely on such critical pathways, which help the plants reestablish the various processes, including ionic, osmotic, and reactive oxygen species [27]. It is necessary for the plants that grow under salt stress conditions to re-adjust the different biochemical and physiological processes involved under salt stress, and plants have to adjust their physiological and biochemical processes, engaged in modifying not only the ionic but also the osmotic homeostasis [29].
Several studies have shown that every hormone present in the plant does not play only a biological role in the plant, but also plays a vital role in various important stages, such as tissue formation and other physiological processes [30, 31]. These phytohormones can act either near to or remove from the site of synthesis to regulate responses to environmental stimuli or genetically programmed developmental changes [32]. So, hormones play a vital role in facilitating plant response to various abiotic stresses. The plant may try to spurt or survive under stress conditions and may also decrease plant growth. Thus, the plant focuses on its resources on withstanding the stress [33]. Abiotic stresses may cause a different type of damage, often leading to adjustments in production, supply, and signal transductions of growth along with stress hormones that can promote definite protective mechanisms [26]. Awareness of a stress signal generates the signal transduction pours in plants with hormones acting as the baseline transducers [34].
4. Participation of plant hormones in heat and cold stress tolerance
Plants have established a different but extraordinary ability to acclimatize the harsh environment and flourish in habitats categorized by abiotic stresses, for example, temperature extremes [35]. Both exogenous and endogenous environmental factors are involved in regulating plant growth and development [8]. All the exogenous environmental factors (temperature, light, moisture, and atmospheric CO2) must be present at an optimal level to regulate the metabolic process. Temperature is one of the most important factors among all environmental factors because it plays a dynamic role in regulating the phenological development of a crop plant [36]. Temperature beyond the “physiological optimum” that affects a plant’s optimal growth is usually known as “high temperature” for that particular plant. The participation of hormones in the plant response to heat stress can be examined in many different ways. Associate approaches such as short-term heat shock with enormously high-temperature and heat acclimation study reveal plants to minor heat stress previously imposing great heat stress and long-term high-temperature treatment [37].
Some important crops (annual) such as wheat, oats, barley, and pea show a substantial degree of intrinsic freezing tolerance, which can be further enhanced by using complex signaling events. On the other hand, some species such as maize, rice, and tomato, which belong to temperate or tropical zones, may face severe damage at a chilling temperature [35]. Hormones are chemical messengers and low-molecular-weight complexes that transfer essential information from a production site to the place of action. Regulation of hormonal homeostasis is taken up by different processes such as biosynthesis, catabolism, and their transformation from one place to another. At the same time, the sensitivity is produced due to the presence and response of dedicated receptors determined by the receiving tissue, which pledge the signal transduction action to change the cellular process [38].
Various types and classes of hormones are available that are involved in the different and overlapping functions. Furthermore, hormones manifest different synergistic and antagonistic effects on the synthesis and signaling productions of the other hormones, generating a composite network of hormonal relations [38]. The hormonal signaling system assimilates the peripheral information into endogenous development programs and initiates the stress-responsive pathway leading toward resistance. Hence, it may not be surprising that plants utilize phytohormones to signal cold stress. So, it may be accredited to the fact that hormonal behavior under cold stress conditions is inclined by cross-talk with signaling forces the consulting response to other environmental temptations including light [39] and is also obstructed by endogenous developing programs, especially those, which results in developmental phase transitions [40].
5. Response of plant hormones to drought stress
Although the green revolution has enhanced plant output, the ever-increasing global population and global warming (which is producing drought stress) are again putting a strain on our ability to feed the globe [41]. As a result of catastrophic losses in agricultural output caused by drought stress during the previous few decades, there is a worldwide challenge to enhance the yield and plant drought resistance [42]. Drought is a disaster for agriculture, humankind, and animals alike. Climate change is bringing us closer to a hotter and drier planet. Hence, we urgently need to produce drought-resistant, high-yielding crops [43]. Drought is an important plant stressor that considerably influences plant growth and productivity, resulting in large agricultural production losses [44]. Drought stress causes plants to undergo morphological, physiological, biochemical, and molecular changes [45].
Small compounds such as peptides or hormone are effective in agriculture for fine-tuning drought response pathways while maintaining production. Research initiatives that reveal the physiology of plant responses to drought in model systems and transfer these results to crops will result in novel water-saving measures [46]. Even as the world’s population rises, finding solutions to alleviate agriculture’s “thirst” would lessen competition for freshwater supplies [47]. Exogenous application of hormones improves the endogenous hormone contents that significantly help in improved photosynthetic fluorescence of leaves, plant enzymatic activities, regulates source-sink balance, yields maintenance, and enhances carbon metabolism under the drought stress environment [48].
To reduce the effect of drought stress on plants, these mechanisms may include the mitogen-activated protein kinases (MAPK) signaling system, calcium signaling route, transcription factor modulation, and higher levels of antioxidant enzymes and other chemicals [49]. Exogenous application of chemicals (nitric oxide, 24-epibrassinolide, proline, glycine betaine), plant breeding, and transgenic approaches is under consideration by scientists to enhance these systems [50]. Early-stage application helps to control drought stress, and spraying 6-BA has capability to regulate the content of endogenous hormones and improve photosynthetic characteristics of sweet potato, and thus effectively alleviates the loss of yield [51]. Under drought condition, seed treatment of plant hormones, maize germination percentage, and seedling growth were enhanced significantly [52] amid to improved drought resistance.
6. Involvement of phytohormones in resetting plant-pest interaction
Many aspects of plant growth and responses to biotic and abiotic stressors are influenced by phytohormones [53]. Jasmonates, ethylene, and salicylic acid are the three primary phytohormones that mediate defensive responses to pests and diseases. Other hormones’ involvement in defensive signaling has recently been discovered. Abscisic acid, a hormone generally linked with abiotic stress reactions, has been identified as a critical fine-tune regulator of defenses [54].
Plants have their defense systems to combat pests’ invasions. It has limited pre-existing defense systems, and the majority of the defense response is triggered only after an insect or disease has infected it. Pests’ attacks are repelled both directly and indirectly by plants. Many of these defenses are controlled by signaling pathways in which phytohormones play a significant role. Insects evolve methods to overcome the plant obstacles simultaneously, resulting in an intriguing co-evolution of plant-pest interactions. Biological immune systems require the ability to sense and respond, but to what degree can plants recognize and respond to pests specifically is integral? The jasmonate route has emerged as a critical signaling mechanism for integrating data from the plant-pest contact into broad-spectrum defensive responses [55]. A proper defense reaction to a biotic danger requires early detection. Pathogens are identified when pattern recognition receptors (PRRs) on the surface of the host plant cell detects conserved patterns of microbial molecules termed microbe- or pathogen-associated molecular patterns (MAMPs or PAMPs), resulting in PAMP-triggered immunity (PTI). PRRs also identify damage-associated molecular patterns (DAMPs) that are endogenous chemicals generated by the plant after infection and induce defensive responses [56]. Pathogens can avoid this innate immune response by using effector proteins that decrease PTI when delivered into the host cell. Disease resistance proteins identified in some plant genotypes precisely detect pathogen effectors, resulting in effector-triggered immunity (ETI) [57]. However, both PTI and ETI models are considered as a generalization [58]. Involved receptors and ligands in molecular identification have empowered conclusions about the specificity of recognition in plant-pathogen interactions. Usually, ETI is activated by highly pathogen-specific chemicals, whereas PTI is based on the non-specific detection of common microbial molecules [59].
In contrast to diseases, insects are vastly complex multicellular animals with a wide range of lives and cognitive behaviors. The plant may use cues from these patterns to identify the threat of herbivory and establish appropriate defense responses [60]. When plant tissue integrity is disrupted during insect feeding, jasmonoyl-L-isoleucine (JA-Ile) is produced, and a well-defined signal transduction chain is activated, leading to the transcriptional activation of defensive responses [61]. Beyond jasmonates, how can plants fine-tune their defensive mechanism to mount herbivore-specific responses? There are two possible responses to this topic. The first is that plants may employ jasmonates-independent, parallel pathways to generate unique response patterns. Second, specificity may be mediated by the activation of jasmonates-response spatiotemporal modulators. The first premise is supported by research on the tomato’s recognition and response mechanism to the potato aphid Macrosiphum euphorbiae. Mi-1, a potential receptor, causes salicylic acid-mediated signaling [62] and resistance independent of the jasmonate system [63]. Plant recognition and response to many different hemipterans appear to follow a similar pattern, implying that plants utilize jasmonates separate hormone response mechanisms to develop specialized resistance to phloem-feeding [64].
The capacity of one participant to notice and respond to cues provided by the other is a recurring topic in all realms of plant-pest biology. This information flow serves as a great focal point for revealing fundamental chemical and molecular principles of plant-pest interactions. Nonetheless, the research supports several broad conclusions concerning plant-pest interactions’ distinctiveness. To begin, plants recognize distinct arthropods by combining various environmental signals, ranging from mechanical stimulation by insects moving on plant surfaces to contact with glandular components during feeding. Second, herbivore sensing activates regulatory responses involving several phytohormones, with the Jasmonate pathway playing a pivotal role in host resistance. Third, despite the significant conservation of Jasmonate signaling, it is becoming increasingly evident that several hormone response pathways interact to transform initial sensory events into suitable responses that promote plant fitness in the face of aggressive aggressors. Anyhow, understanding the impacts of phytohormones at the whole plant level is undoubtedly important, and the future study presents an intriguing challenge.
7. Future prospects and challenges
Plant hormones have proven themselves effective against biotic and abiotic stresses that emerged due to climate change. However, it is a challenge for researchers and industrialists to prepare cost-effective products that can be used on a large scale. Moreover, salicylic acid is a defensive hormone, but its biosynthesis pathway for salicylic acid is still incomplete; thus, this section requires attention. Furthermore, various parts of the globe face more biotic/abiotic stress, but we still lack understanding of the response of jasmonates against multiple stress conditions. In addition, optimizing the endogenous levels of plant hormones to improve the stress-responsive crosstalk mechanisms between multiple hormones is still a research gap.
8. Conclusion
The increasing population requires the scientific community to suggest effective technologies for food security. Besides this, climate change is a global problem that adversely impacts the agriculture sector and creates hurdles for agriculture sustainability. Plant hormones within the plants or prepared by the plants have a promising role in tackling these challenges. It enables the plants to tolerate the biotic and abiotic stresses as well as improve agriculture productivity. Therefore, understanding the mechanism and endogenous application of plant hormones can be an effective tool against climate change and its driven problems.
Conflict of interest
The authors have no conflict of interests to declare.
\n',keywords:"plant stress, abiotic factors, biostimulants, plant growth regulators, agricultural production",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/80752.pdf",chapterXML:"https://mts.intechopen.com/source/xml/80752.xml",downloadPdfUrl:"/chapter/pdf-download/80752",previewPdfUrl:"/chapter/pdf-preview/80752",totalDownloads:58,totalViews:0,totalCrossrefCites:0,dateSubmitted:"November 9th 2021",dateReviewed:"January 11th 2022",datePrePublished:"March 6th 2022",datePublished:"May 25th 2022",dateFinished:"March 6th 2022",readingETA:"0",abstract:"Climate change is an emerging issue for modern agriculture and has generated biotic and abiotic stresses for plants such as cold, high temperature, heat, drought, uneven rainfall, and UV radiations. In addition to these, serious stress factors are emerging related to water availability, nutrient cycling, salinity-sodicity, and pest attacks. In recent years, such phenomena have attracted the research community to avoid the fatal influence of climate change on crop production and obtain more food helping in fulfillment of increasing food demand of population surge. The anthropogenic activities in the agroecosystem are among the major causes for global warming and proportion in climate change. Therefore, it is assumed that identifying various plant hormones and their utilization to improve plant metabolic activities would help maintain plant growth, survival, and production under severe climate change circumstances. This chapter focuses on identifying the key aspects of plant hormones to retard the negative impacts of climate change and support sustainable agriculture.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/80752",risUrl:"/chapter/ris/80752",signatures:"Muhammad Amjad Bashir, Qurat-Ul-Ain Raza, Hafiz Muhammad Ali Raza, Muhammad Umair Sial, Abdur Rehim, Kashif Ali Khan, Muhammad Ijaz and Muhammad Wasif",book:{id:"10940",type:"book",title:"Plant Hormones",subtitle:"Recent Advances, New Perspectives and Applications",fullTitle:"Plant Hormones - Recent Advances, New Perspectives and Applications",slug:"plant-hormones-recent-advances-new-perspectives-and-applications",publishedDate:"May 25th 2022",bookSignature:"Christophe Hano",coverURL:"https://cdn.intechopen.com/books/images_new/10940.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",isbn:"978-1-80355-028-2",printIsbn:"978-1-80355-027-5",pdfIsbn:"978-1-80355-029-9",isAvailableForWebshopOrdering:!0,editors:[{id:"313856",title:"Dr.",name:"Christophe",middleName:"F.E.",surname:"Hano",slug:"christophe-hano",fullName:"Christophe Hano"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"315028",title:"Dr.",name:"Muhammad",middleName:null,surname:"Ijaz",fullName:"Muhammad Ijaz",slug:"muhammad-ijaz",email:"muhammad.ijaz@bzu.edu.pk",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"345126",title:"Dr.",name:"Abdur",middleName:null,surname:"Rehim",fullName:"Abdur Rehim",slug:"abdur-rehim",email:"abdur.rehim@bzu.edu.pk",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"417042",title:"Dr.",name:"Muhammad Amjad",middleName:null,surname:"Bashir",fullName:"Muhammad Amjad Bashir",slug:"muhammad-amjad-bashir",email:"amjad.bashir941@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Bahauddin Zakariya University",institutionURL:null,country:{name:"Pakistan"}}},{id:"417043",title:"Ms.",name:"Qurat-Ul-Ain",middleName:null,surname:"Raza",fullName:"Qurat-Ul-Ain Raza",slug:"qurat-ul-ain-raza",email:"quratulain1111@yahoo.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Bahauddin Zakariya University",institutionURL:null,country:{name:"Pakistan"}}},{id:"417044",title:"Mr.",name:"Hafiz Muhammad Ali",middleName:null,surname:"Raza",fullName:"Hafiz Muhammad Ali Raza",slug:"hafiz-muhammad-ali-raza",email:"maraza1524@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Bahauddin Zakariya University",institutionURL:null,country:{name:"Pakistan"}}},{id:"444263",title:"Dr.",name:"Muhammad Umair",middleName:null,surname:"Sial",fullName:"Muhammad Umair Sial",slug:"muhammad-umair-sial",email:"umair.sial@mnsuam.edu.pk",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:null},{id:"444265",title:"Dr.",name:"Kashif Ali",middleName:null,surname:"Khan",fullName:"Kashif Ali Khan",slug:"kashif-ali-khan",email:"rana13tda@yahoo.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Bahauddin Zakariya University",institutionURL:null,country:{name:"Pakistan"}}},{id:"444266",title:"Mr.",name:"Muhammad",middleName:null,surname:"Wasif",fullName:"Muhammad Wasif",slug:"muhammad-wasif",email:"mhrwasi@gmail.com",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institution:{name:"Bahauddin Zakariya University",institutionURL:null,country:{name:"Pakistan"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Interaction of plant hormones with plant physiology",level:"1"},{id:"sec_3",title:"3. Role of plant hormone in adaptation to salt stress",level:"1"},{id:"sec_4",title:"4. Participation of plant hormones in heat and cold stress tolerance",level:"1"},{id:"sec_5",title:"5. Response of plant hormones to drought stress",level:"1"},{id:"sec_6",title:"6. Involvement of phytohormones in resetting plant-pest interaction",level:"1"},{id:"sec_7",title:"7. Future prospects and challenges",level:"1"},{id:"sec_8",title:"8. Conclusion",level:"1"},{id:"sec_12",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Arora NK. Impact of climate change on agriculture production and its sustainable solutions. Environmental Sustainability. 2019;2:95-96. DOI: 10.1007/s42398-019-00078-w'},{id:"B2",body:'Aryal JP, Sapkota TB, Khurana R, Khatri-Chhetri A, Rahut DB, Jat ML. 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DOI: 10.1016/j.crvi.2010.04.003'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Muhammad Amjad Bashir",address:"amjad.bashir941@gmail.com",affiliation:'
College of Agriculture, Bahadur Sub-Campus Layyah, Bahauddin Zakariya University, Pakistan
College of Agriculture, Bahadur Sub-Campus Layyah, Bahauddin Zakariya University, Pakistan
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It has been long appreciated that NF1 is often associated with endocrine disorders. In this chapter, we will discuss the endocrine disorders associated with NF1. The most common endocrinological disorders in NF1 are short stature with or without growth hormone deficiency, central precocious puberty, growth hormone excess. 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UK Research and Innovation (former Research Councils UK (RCUK) - including AHRC, BBSRC, ESRC, EPSRC, MRC, NERC, STFC.) Processing charges for books/book chapters can be covered through RCUK block grants which are allocated to most universities in the UK, which then handle the OA publication funding requests. It is at the discretion of the university whether it will approve the request.)
UK Research and Innovation (former Research Councils UK (RCUK) - including AHRC, BBSRC, ESRC, EPSRC, MRC, NERC, STFC.) Processing charges for books/book chapters can be covered through RCUK block grants which are allocated to most universities in the UK, which then handle the OA publication funding requests. It is at the discretion of the university whether it will approve the request.)
Wellcome Trust (Funding available only to Wellcome-funded researchers/grantees)
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Much of biochemistry is devoted to enzymes, proteins that catalyze chemical reactions, enzyme structures, mechanisms of action and their roles within cells. Biochemistry also studies small signaling molecules, coenzymes, inhibitors, vitamins, and hormones, which play roles in life processes. Biochemical experimentation, besides coopting classical chemistry methods, e.g., chromatography, adopted new techniques, e.g., X-ray diffraction, electron microscopy, NMR, radioisotopes, and developed sophisticated microbial genetic tools, e.g., auxotroph mutants and their revertants, fermentation, etc. More recently, biochemistry embraced the ‘big data’ omics systems. Initial biochemical studies have been exclusively analytic: dissecting, purifying, and examining individual components of a biological system; in the apt words of Efraim Racker (1913 –1991), “Don’t waste clean thinking on dirty enzymes.” Today, however, biochemistry is becoming more agglomerative and comprehensive, setting out to integrate and describe entirely particular biological systems. The ‘big data’ metabolomics can define the complement of small molecules, e.g., in a soil or biofilm sample; proteomics can distinguish all the comprising proteins, e.g., serum; metagenomics can identify all the genes in a complex environment, e.g., the bovine rumen. 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Dr. Blumenberg’s research is focused on the epidermis, expression of keratin genes, transcription profiling, keratinocyte differentiation, inflammatory diseases and cancers, and most recently the effects of the microbiome on the skin. 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Her research interests include archaea metabolism, enzymes purification and characterization, gene regulation, carotenoids and bioplastics production, antioxidant\ncompounds, waste water treatments, and brines bioremediation.\nRosa María’s other roles include editorial board member for several journals related\nto biochemistry, reviewer for more than 60 journals (biochemistry, molecular biology, biotechnology, chemistry and microbiology) and president of several organizing committees in international meetings related to the N-cycle or respiratory processes.",institutionString:null,institution:{name:"University of Alicante",institutionURL:null,country:{name:"Spain"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"79367",title:"Dr.",name:"Ana Isabel",middleName:null,surname:"Flores",slug:"ana-isabel-flores",fullName:"Ana Isabel Flores",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRpIOQA0/Profile_Picture_1632418099564",institutionString:null,institution:{name:"Hospital Universitario 12 De Octubre",institutionURL:null,country:{name:"Spain"}}},{id:"328234",title:"Ph.D.",name:"Christian",middleName:null,surname:"Palavecino",slug:"christian-palavecino",fullName:"Christian Palavecino",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000030DhEhQAK/Profile_Picture_1628835318625",institutionString:null,institution:{name:"Central University of Chile",institutionURL:null,country:{name:"Chile"}}},{id:"186585",title:"Dr.",name:"Francisco Javier",middleName:null,surname:"Martin-Romero",slug:"francisco-javier-martin-romero",fullName:"Francisco Javier Martin-Romero",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSB3HQAW/Profile_Picture_1631258137641",institutionString:null,institution:{name:"University of Extremadura",institutionURL:null,country:{name:"Spain"}}}]},{id:"15",title:"Chemical Biology",coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",slug:"sukru-beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",biography:"Dr. Şükrü Beydemir obtained a BSc in Chemistry in 1995 from Yüzüncü Yıl University, MSc in Biochemistry in 1998, and PhD in Biochemistry in 2002 from Atatürk University, Turkey. 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He is a member of the Turkish Biochemical Society, American Chemical Society, and German Genetics society. Dr. Ekinci published around ninety scientific papers, reviews and book chapters, and presented several conferences to scientists. He has received numerous publication awards from several scientific councils. 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More recently, Prof. Iadarola was involved in developing techniques such as two-dimensional electrophoresis coupled to liquid chromatography/mass spectrometry (2DE-LC/MS) for the proteomic analysis of biological fluids aimed at the identification of potential biomarkers of different lung diseases. He is the author of about 150 publications (According to Scopus: H-Index: 23; Total citations: 1568- According to WOS: H-Index: 20; Total Citations: 1296) of peer-reviewed international journals. He is a Consultant Reviewer for several journals, including the Journal of Chromatography A, Journal of Chromatography B, Plos ONE, Proteomes, International Journal of Molecular Science, Biotech, Electrophoresis, and others. 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She gained considerable experience in developing and validating new methodologies whose applications allowed her to determine both the amount of biomarkers (Desmosine and Isodesmosine) in the urine of patients affected by COPD, and the activity of proteolytic enzymes (HNE, Cathepsin G, Pseudomonas aeruginosa elastase) in the sputa of these patients. Simona Viglio was also involved in research dealing with the supplementation of amino acids in patients with brain injury and chronic heart failure. She is presently engaged in the development of 2-DE and LC-MS techniques for the study of proteomics in biological fluids. The aim of this research is the identification of potential biomarkers of lung diseases. 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His fields of interest are anterior segment disease, keratoconus, glaucoma, corneal dystrophies, and cataracts. His research topics include\nintraocular lens power calculation, eye modification induced by refractive surgery, glaucoma progression, and validation of new diagnostic devices in ophthalmology. \nHe has published more than 100 papers in international and Italian scientific journals, more than 60 in journals with impact factors, and chapters in international and Italian books. He has also edited two international books and authored more than 150 communications or posters for the most important international and Italian ophthalmology conferences.",institutionString:'University of Campania "Luigi Vanvitelli"',institution:{name:'University of Campania "Luigi Vanvitelli"',institutionURL:null,country:{name:"Italy"}}}]},{type:"book",id:"7560",title:"Non-Invasive Diagnostic Methods",subtitle:"Image Processing",coverURL:"https://cdn.intechopen.com/books/images_new/7560.jpg",slug:"non-invasive-diagnostic-methods-image-processing",publishedDate:"December 19th 2018",editedByType:"Edited by",bookSignature:"Mariusz Marzec and Robert Koprowski",hash:"d92fd8cf5a90a47f2b8a310837a5600e",volumeInSeries:3,fullTitle:"Non-Invasive Diagnostic Methods - Image Processing",editors:[{id:"253468",title:"Dr.",name:"Mariusz",middleName:null,surname:"Marzec",slug:"mariusz-marzec",fullName:"Mariusz Marzec",profilePictureURL:"https://mts.intechopen.com/storage/users/253468/images/system/253468.png",biography:"An assistant professor at Department of Biomedical Computer Systems, at Institute of Computer Science, Silesian University in Katowice. 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He started his academic career as a Research Assistant in the Department of Biochemistry at Kafkas University. In 2019, he completed his Ph.D. program in the Department of Biochemistry at the Institute of Health Sciences. He is currently working at the Department of Biochemistry, Kafkas University. He has 27 published research articles in academic journals, 11 book chapters, and 37 papers. He took part in 10 academic projects. He served as a reviewer for many articles. He still serves as a member of the review board in many academic journals.",institutionString:null,institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"178366",title:"Associate Prof.",name:"Volkan",middleName:null,surname:"Gelen",slug:"volkan-gelen",fullName:"Volkan Gelen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/178366/images/system/178366.jpg",biography:"Volkan Gelen is a Physiology specialist who received his veterinary degree from Kafkas University in 2011. Between 2011-2015, he worked as an assistant at Atatürk University, Faculty of Veterinary Medicine, Department of Physiology. In 2016, he joined Kafkas University, Faculty of Veterinary Medicine, Department of Physiology as an assistant professor. Dr. Gelen has been engaged in various academic activities at Kafkas University since 2016. There he completed 5 projects and has 3 ongoing projects. He has 60 articles published in scientific journals and 20 poster presentations in scientific congresses. His research interests include physiology, endocrine system, cancer, diabetes, cardiovascular system diseases, and isolated organ bath system studies.",institutionString:"Kafkas University",institution:{name:"Kafkas University",country:{name:"Turkey"}}},{id:"418963",title:"Dr.",name:"Augustine Ododo",middleName:"Augustine",surname:"Osagie",slug:"augustine-ododo-osagie",fullName:"Augustine Ododo Osagie",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/418963/images/16900_n.jpg",biography:"Born into the family of Osagie, a prince of the Benin Kingdom. I am currently an academic in the Department of Medical Biochemistry, University of Benin. Part of the duties are to teach undergraduate students and conduct academic research.",institutionString:null,institution:{name:"University of Benin",country:{name:"Nigeria"}}},{id:"192992",title:"Prof.",name:"Shagufta",middleName:null,surname:"Perveen",slug:"shagufta-perveen",fullName:"Shagufta Perveen",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/192992/images/system/192992.png",biography:"Prof. Shagufta Perveen is a Distinguish Professor in the Department of Pharmacognosy, College of Pharmacy, King Saud University, Riyadh, Saudi Arabia. Dr. Perveen has acted as the principal investigator of major research projects funded by the research unit of King Saud University. She has more than ninety original research papers in peer-reviewed journals of international repute to her credit. She is a fellow member of the Royal Society of Chemistry UK and the American Chemical Society of the United States.",institutionString:"King Saud University",institution:{name:"King Saud University",country:{name:"Saudi Arabia"}}},{id:"49848",title:"Dr.",name:"Wen-Long",middleName:null,surname:"Hu",slug:"wen-long-hu",fullName:"Wen-Long Hu",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/49848/images/system/49848.jpg",biography:"Wen-Long Hu is Chief of the Division of Acupuncture, Department of Chinese Medicine at Kaohsiung Chang Gung Memorial Hospital, as well as an adjunct associate professor at Fooyin University and Kaohsiung Medical University. Wen-Long is President of Taiwan Traditional Chinese Medicine Medical Association. He has 28 years of experience in clinical practice in laser acupuncture therapy and 34 years in acupuncture. He is an invited speaker for lectures and workshops in laser acupuncture at many symposiums held by medical associations. He owns the patent for herbal preparation and producing, and for the supercritical fluid-treated needle. Dr. Hu has published three books, 12 book chapters, and more than 30 papers in reputed journals, besides serving as an editorial board member of repute.",institutionString:"Kaohsiung Chang Gung Memorial Hospital",institution:{name:"Kaohsiung Chang Gung Memorial Hospital",country:{name:"Taiwan"}}},{id:"298472",title:"Prof.",name:"Andrey V.",middleName:null,surname:"Grechko",slug:"andrey-v.-grechko",fullName:"Andrey V. Grechko",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/298472/images/system/298472.png",biography:"Andrey Vyacheslavovich Grechko, Ph.D., Professor, is a Corresponding Member of the Russian Academy of Sciences. He graduated from the Semashko Moscow Medical Institute (Semashko National Research Institute of Public Health) with a degree in Medicine (1998), the Clinical Department of Dermatovenerology (2000), and received a second higher education in Psychology (2009). Professor A.V. Grechko held the position of Сhief Physician of the Central Clinical Hospital in Moscow. He worked as a professor at the faculty and was engaged in scientific research at the Medical University. Starting in 2013, he has been the initiator of the creation of the Federal Scientific and Clinical Center for Intensive Care and Rehabilitology, Moscow, Russian Federation, where he also serves as Director since 2015. He has many years of experience in research and teaching in various fields of medicine, is an author/co-author of more than 200 scientific publications, 13 patents, 15 medical books/chapters, including Chapter in Book «Metabolomics», IntechOpen, 2020 «Metabolomic Discovery of Microbiota Dysfunction as the Cause of Pathology».",institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"199461",title:"Prof.",name:"Natalia V.",middleName:null,surname:"Beloborodova",slug:"natalia-v.-beloborodova",fullName:"Natalia V. Beloborodova",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/199461/images/system/199461.jpg",biography:'Natalia Vladimirovna Beloborodova was educated at the Pirogov Russian National Research Medical University, with a degree in pediatrics in 1980, a Ph.D. in 1987, and a specialization in Clinical Microbiology from First Moscow State Medical University in 2004. She has been a Professor since 1996. Currently, she is the Head of the Laboratory of Metabolism, a division of the Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology, Moscow, Russian Federation. N.V. Beloborodova has many years of clinical experience in the field of intensive care and surgery. She studies infectious complications and sepsis. She initiated a series of interdisciplinary clinical and experimental studies based on the concept of integrating human metabolism and its microbiota. Her scientific achievements are widely known: she is the recipient of the Marie E. Coates Award \\"Best lecturer-scientist\\" Gustafsson Fund, Karolinska Institutes, Stockholm, Sweden, and the International Sepsis Forum Award, Pasteur Institute, Paris, France (2014), etc. Professor N.V. Beloborodova wrote 210 papers, five books, 10 chapters and has edited four books.',institutionString:"Federal Research and Clinical Center of Intensive Care Medicine and Rehabilitology",institution:null},{id:"354260",title:"Ph.D.",name:"Tércio Elyan",middleName:"Azevedo",surname:"Azevedo Martins",slug:"tercio-elyan-azevedo-martins",fullName:"Tércio Elyan Azevedo Martins",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/354260/images/16241_n.jpg",biography:"Graduated in Pharmacy from the Federal University of Ceará with the modality in Industrial Pharmacy, Specialist in Production and Control of Medicines from the University of São Paulo (USP), Master in Pharmaceuticals and Medicines from the University of São Paulo (USP) and Doctor of Science in the program of Pharmaceuticals and Medicines by the University of São Paulo. Professor at Universidade Paulista (UNIP) in the areas of chemistry, cosmetology and trichology. Assistant Coordinator of the Higher Course in Aesthetic and Cosmetic Technology at Universidade Paulista Campus Chácara Santo Antônio. Experience in the Pharmacy area, with emphasis on Pharmacotechnics, Pharmaceutical Technology, Research and Development of Cosmetics, acting mainly on topics such as cosmetology, antioxidant activity, aesthetics, photoprotection, cyclodextrin and thermal analysis.",institutionString:null,institution:{name:"University of Sao Paulo",country:{name:"Brazil"}}},{id:"334285",title:"Ph.D. Student",name:"Sameer",middleName:"Kumar",surname:"Jagirdar",slug:"sameer-jagirdar",fullName:"Sameer Jagirdar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/334285/images/14691_n.jpg",biography:"I\\'m a graduate student at the center for biosystems science and engineering at the Indian Institute of Science, Bangalore, India. I am interested in studying host-pathogen interactions at the biomaterial interface.",institutionString:null,institution:{name:"Indian Institute of Science Bangalore",country:{name:"India"}}},{id:"329795",title:"Dr.",name:"Mohd Aftab",middleName:"Aftab",surname:"Siddiqui",slug:"mohd-aftab-siddiqui",fullName:"Mohd Aftab Siddiqui",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/329795/images/15648_n.jpg",biography:"Dr. Mohd Aftab Siddiqui is currently working as Assistant Professor in the Faculty of Pharmacy, Integral University, Lucknow for the last 6 years. He has completed his Doctor in Philosophy (Pharmacology) in 2020 from Integral University, Lucknow. He completed his Bachelor in Pharmacy in 2013 and Master in Pharmacy (Pharmacology) in 2015 from Integral University, Lucknow. He is the gold medalist in Bachelor and Master degree. He qualified GPAT -2013, GPAT -2014, and GPAT 2015. His area of research is Pharmacological screening of herbal drugs/ natural products in liver and cardiac diseases. He has guided many M. Pharm. research projects. He has many national and international publications.",institutionString:"Integral University",institution:null},{id:"255360",title:"Dr.",name:"Usama",middleName:null,surname:"Ahmad",slug:"usama-ahmad",fullName:"Usama Ahmad",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/255360/images/system/255360.png",biography:"Dr. Usama Ahmad holds a specialization in Pharmaceutics from Amity University, Lucknow, India. He received his Ph.D. degree from Integral University. Currently, he’s working as an Assistant Professor of Pharmaceutics in the Faculty of Pharmacy, Integral University. From 2013 to 2014 he worked on a research project funded by SERB-DST, Government of India. He has a rich publication record with more than 32 original articles published in reputed journals, 3 edited books, 5 book chapters, and a number of scientific articles published in ‘Ingredients South Asia Magazine’ and ‘QualPharma Magazine’. He is a member of the American Association for Cancer Research, International Association for the Study of Lung Cancer, and the British Society for Nanomedicine. Dr. Ahmad’s research focus is on the development of nanoformulations to facilitate the delivery of drugs that aim to provide practical solutions to current healthcare problems.",institutionString:"Integral University",institution:{name:"Integral University",country:{name:"India"}}},{id:"30568",title:"Prof.",name:"Madhu",middleName:null,surname:"Khullar",slug:"madhu-khullar",fullName:"Madhu Khullar",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/30568/images/system/30568.jpg",biography:"Dr. Madhu Khullar is a Professor of Experimental Medicine and Biotechnology at the Post Graduate Institute of Medical Education and Research, Chandigarh, India. She completed her Post Doctorate in hypertension research at the Henry Ford Hospital, Detroit, USA in 1985. She is an editor and reviewer of several international journals, and a fellow and member of several cardiovascular research societies. Dr. Khullar has a keen research interest in genetics of hypertension, and is currently studying pharmacogenetics of hypertension.",institutionString:"Post Graduate Institute of Medical Education and Research",institution:{name:"Post Graduate Institute of Medical Education and Research",country:{name:"India"}}},{id:"223233",title:"Prof.",name:"Xianquan",middleName:null,surname:"Zhan",slug:"xianquan-zhan",fullName:"Xianquan Zhan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/223233/images/system/223233.png",biography:"Xianquan Zhan received his MD and Ph.D. in Preventive Medicine at West China University of Medical Sciences. He received his post-doctoral training in oncology and cancer proteomics at the Central South University, China, and the University of Tennessee Health Science Center (UTHSC), USA. He worked at UTHSC and the Cleveland Clinic in 2001–2012 and achieved the rank of associate professor at UTHSC. Currently, he is a full professor at Central South University and Shandong First Medical University, and an advisor to MS/PhD students and postdoctoral fellows. He is also a fellow of the Royal Society of Medicine and European Association for Predictive Preventive Personalized Medicine (EPMA), a national representative of EPMA, and a member of the American Society of Clinical Oncology (ASCO) and the American Association for the Advancement of Sciences (AAAS). He is also the editor in chief of International Journal of Chronic Diseases & Therapy, an associate editor of EPMA Journal, Frontiers in Endocrinology, and BMC Medical Genomics, and a guest editor of Mass Spectrometry Reviews, Frontiers in Endocrinology, EPMA Journal, and Oxidative Medicine and Cellular Longevity. He has published more than 148 articles, 28 book chapters, 6 books, and 2 US patents in the field of clinical proteomics and biomarkers.",institutionString:"Shandong First Medical University",institution:{name:"Affiliated Hospital of Shandong Academy of Medical Sciences",country:{name:"China"}}},{id:"297507",title:"Dr.",name:"Charles",middleName:"Elias",surname:"Assmann",slug:"charles-assmann",fullName:"Charles Assmann",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/297507/images/system/297507.jpg",biography:"Charles Elias Assmann is a biologist from Federal University of Santa Maria (UFSM, Brazil), who spent some time abroad at the Ludwig-Maximilians-Universität München (LMU, Germany). He has Masters Degree in Biochemistry (UFSM), and is currently a PhD student at Biochemistry at the Department of Biochemistry and Molecular Biology of the UFSM. His areas of expertise include: Biochemistry, Molecular Biology, Enzymology, Genetics and Toxicology. He is currently working on the following subjects: Aluminium toxicity, Neuroinflammation, Oxidative stress and Purinergic system. Since 2011 he has presented more than 80 abstracts in scientific proceedings of national and international meetings. Since 2014, he has published more than 20 peer reviewed papers (including 4 reviews, 3 in Portuguese) and 2 book chapters. He has also been a reviewer of international journals and ad hoc reviewer of scientific committees from Brazilian Universities.",institutionString:"Universidade Federal de Santa Maria",institution:{name:"Universidade Federal de Santa Maria",country:{name:"Brazil"}}},{id:"217850",title:"Dr.",name:"Margarete Dulce",middleName:null,surname:"Bagatini",slug:"margarete-dulce-bagatini",fullName:"Margarete Dulce Bagatini",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/217850/images/system/217850.jpeg",biography:"Dr. Margarete Dulce Bagatini is an associate professor at the Federal University of Fronteira Sul/Brazil. She has a degree in Pharmacy and a PhD in Biological Sciences: Toxicological Biochemistry. She is a member of the UFFS Research Advisory Committee\nand a member of the Biovitta Research Institute. She is currently:\nthe leader of the research group: Biological and Clinical Studies\nin Human Pathologies, professor of postgraduate program in\nBiochemistry at UFSC and postgraduate program in Science and Food Technology at\nUFFS. She has experience in the area of pharmacy and clinical analysis, acting mainly\non the following topics: oxidative stress, the purinergic system and human pathologies, being a reviewer of several international journals and books.",institutionString:"Universidade Federal da Fronteira Sul",institution:{name:"Universidade Federal da Fronteira Sul",country:{name:"Brazil"}}},{id:"226275",title:"Ph.D.",name:"Metin",middleName:null,surname:"Budak",slug:"metin-budak",fullName:"Metin Budak",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/226275/images/system/226275.jfif",biography:"Metin Budak, MSc, PhD is an Assistant Professor at Trakya University, Faculty of Medicine. He has been Head of the Molecular Research Lab at Prof. Mirko Tos Ear and Hearing Research Center since 2018. His specializations are biophysics, epigenetics, genetics, and methylation mechanisms. He has published around 25 peer-reviewed papers, 2 book chapters, and 28 abstracts. He is a member of the Clinical Research Ethics Committee and Quantification and Consideration Committee of Medicine Faculty. His research area is the role of methylation during gene transcription, chromatin packages DNA within the cell and DNA repair, replication, recombination, and gene transcription. His research focuses on how the cell overcomes chromatin structure and methylation to allow access to the underlying DNA and enable normal cellular function.",institutionString:"Trakya University",institution:{name:"Trakya University",country:{name:"Turkey"}}},{id:"243049",title:"Dr.",name:"Anca",middleName:null,surname:"Pantea Stoian",slug:"anca-pantea-stoian",fullName:"Anca Pantea Stoian",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/243049/images/system/243049.jpg",biography:"Anca Pantea Stoian is a specialist in diabetes, nutrition, and metabolic diseases as well as health food hygiene. She also has competency in general ultrasonography.\n\nShe is an associate professor in the Diabetes, Nutrition and Metabolic Diseases Department, Carol Davila University of Medicine and Pharmacy, Bucharest, Romania. She has been chief of the Hygiene Department, Faculty of Dentistry, at the same university since 2019. Her interests include micro and macrovascular complications in diabetes and new therapies. Her research activities focus on nutritional intervention in chronic pathology, as well as cardio-renal-metabolic risk assessment, and diabetes in cancer. She is currently engaged in developing new therapies and technological tools for screening, prevention, and patient education in diabetes. \n\nShe is a member of the European Association for the Study of Diabetes, Cardiometabolic Academy, CEDA, Romanian Society of Diabetes, Nutrition and Metabolic Diseases, Romanian Diabetes Federation, and Association for Renal Metabolic and Nutrition studies. She has authored or co-authored 160 papers in national and international peer-reviewed journals.",institutionString:null,institution:{name:"Carol Davila University of Medicine and Pharmacy",country:{name:"Romania"}}},{id:"279792",title:"Dr.",name:"João",middleName:null,surname:"Cotas",slug:"joao-cotas",fullName:"João Cotas",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/279792/images/system/279792.jpg",biography:"Graduate and master in Biology from the University of Coimbra.\n\nI am a research fellow at the Macroalgae Laboratory Unit, in the MARE-UC – Marine and Environmental Sciences Centre of the University of Coimbra. My principal function is the collection, extraction and purification of macroalgae compounds, chemical and bioactive characterization of the compounds and algae extracts and development of new methodologies in marine biotechnology area. \nI am associated in two projects: one consists on discovery of natural compounds for oncobiology. The other project is the about the natural compounds/products for agricultural area.\n\nPublications:\nCotas, J.; Figueirinha, A.; Pereira, L.; Batista, T. 2018. An analysis of the effects of salinity on Fucus ceranoides (Ochrophyta, Phaeophyceae), in the Mondego River (Portugal). Journal of Oceanology and Limnology. in press. DOI: 10.1007/s00343-019-8111-3",institutionString:"Faculty of Sciences and Technology of University of Coimbra",institution:null},{id:"279788",title:"Dr.",name:"Leonel",middleName:null,surname:"Pereira",slug:"leonel-pereira",fullName:"Leonel Pereira",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/279788/images/system/279788.jpg",biography:"Leonel Pereira has an undergraduate degree in Biology, a Ph.D. in Biology (specialty in Cell Biology), and a Habilitation degree in Biosciences (specialization in Biotechnology) from the Faculty of Science and Technology, University of Coimbra, Portugal, where he is currently a professor. In addition to teaching at this university, he is an integrated researcher at the Marine and Environmental Sciences Center (MARE), Portugal. His interests include marine biodiversity (algae), marine biotechnology (algae bioactive compounds), and marine ecology (environmental assessment). Since 2008, he has been the author and editor of the electronic publication MACOI – Portuguese Seaweeds Website (www.seaweeds.uc.pt). He is also a member of the editorial boards of several scientific journals. Dr. Pereira has edited or authored more than 20 books, 100 journal articles, and 45 book chapters. He has given more than 100 lectures and oral communications at various national and international scientific events. He is the coordinator of several national and international research projects. In 1998, he received the Francisco de Holanda Award (Honorable Mention) and, more recently, the Mar Rei D. Carlos award (18th edition). He is also a winner of the 2016 CHOICE Award for an outstanding academic title for his book Edible Seaweeds of the World. In 2020, Dr. Pereira received an Honorable Mention for the Impact of International Publications from the Web of Science",institutionString:"University of Coimbra",institution:{name:"University of Coimbra",country:{name:"Portugal"}}},{id:"61946",title:"Dr.",name:"Carol",middleName:null,surname:"Bernstein",slug:"carol-bernstein",fullName:"Carol Bernstein",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/61946/images/system/61946.jpg",biography:"Carol Bernstein received her PhD in Genetics from the University of California (Davis). She was a faculty member at the University of Arizona College of Medicine for 43 years, retiring in 2011. Her research interests focus on DNA damage and its underlying role in sex, aging and in the early steps of initiation and progression to cancer. In her research, she had used organisms including bacteriophage T4, Neurospora crassa, Schizosaccharomyces pombe and mice, as well as human cells and tissues. She authored or co-authored more than 140 scientific publications, including articles in major peer reviewed journals, book chapters, invited reviews and one book.",institutionString:"University of Arizona",institution:{name:"University of Arizona",country:{name:"United States of America"}}},{id:"182258",title:"Dr.",name:"Ademar",middleName:"Pereira",surname:"Serra",slug:"ademar-serra",fullName:"Ademar Serra",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/182258/images/system/182258.jpeg",biography:"Dr. Serra studied Agronomy on Universidade Federal de Mato Grosso do Sul (UFMS) (2005). He received master degree in Agronomy, Crop Science (Soil fertility and plant nutrition) (2007) by Universidade Federal da Grande Dourados (UFGD), and PhD in agronomy (Soil fertility and plant nutrition) (2011) from Universidade Federal da Grande Dourados / Escola Superior de Agricultura Luiz de Queiroz (UFGD/ESALQ-USP). Dr. Serra is currently working at Brazilian Agricultural Research Corporation (EMBRAPA). His research focus is on mineral nutrition of plants, crop science and soil science. Dr. Serra\\'s current projects are soil organic matter, soil phosphorus fractions, compositional nutrient diagnosis (CND) and isometric log ratio (ilr) transformation in compositional data analysis.",institutionString:"Brazilian Agricultural Research Corporation",institution:{name:"Brazilian Agricultural Research Corporation",country:{name:"Brazil"}}}]}},subseries:{item:{id:"23",type:"subseries",title:"Computational Neuroscience",keywords:"Single-Neuron Modeling, Sensory Processing, Motor Control, Memory and Synaptic Pasticity, Attention, Identification, Categorization, Discrimination, Learning, Development, Axonal Patterning and Guidance, Neural Architecture, Behaviours and Dynamics of Networks, Cognition and the Neuroscientific Basis of Consciousness",scope:"Computational neuroscience focuses on biologically realistic abstractions and models validated and solved through computational simulations to understand principles for the development, structure, physiology, and ability of the nervous system. This topic is dedicated to biologically plausible descriptions and computational models - at various abstraction levels - of neurons and neural systems. This includes, but is not limited to: single-neuron modeling, sensory processing, motor control, memory, and synaptic plasticity, attention, identification, categorization, discrimination, learning, development, axonal patterning, guidance, neural architecture, behaviors, and dynamics of networks, cognition and the neuroscientific basis of consciousness. 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