IntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
\\n\\n
IntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
With the desire to make book publishing more relevant for the digital age and offer innovative Open Access publishing options, we are thrilled to announce the launch of our new publishing format: IntechOpen Book Series.
\n\n
Designed to cover fast-moving research fields in rapidly expanding areas, our Book Series feature a Topic structure allowing us to present the most relevant sub-disciplines. Book Series are headed by Series Editors, and a team of Topic Editors supported by international Editorial Board members. Topics are always open for submissions, with an Annual Volume published each calendar year.
\n\n
After a robust peer-review process, accepted works are published quickly, thanks to Online First, ensuring research is made available to the scientific community without delay.
\n\n
Our innovative Book Series format brings you:
\n\n
\n\t
Topic Focused Publications - Each topic showcases high impact subject areas
\n\t
Renowned Editorial Expertise - Series Editors, Topic Editors, and a team of international Board Members that permanently support each Book Series
\n\t
Fast Publishing - quick turnaround which is unique for book publishing
\n\t
The benefit of ISSN and ISBN for increased citation and indexing possibilities
\n
\n\n\n\n
IntechOpen Book Series will also publish a program of research-driven Thematic Edited Volumes that focus on specific areas and allow for a more in-depth overview of a particular subject.
\n\n
IntechOpen Book Series will be launching regularly to offer our authors and editors exciting opportunities to publish their research Open Access. We will begin by relaunching some of our existing Book Series in this innovative book format, and will expand in 2022 into rapidly growing research fields that are driving and advancing society.
We invite you to explore our IntechOpen Book Series, find the right publishing program for you and reach your desired audience in record time.
\n\n
Note: Edited in October 2021
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1. Introduction
Non-alcoholic fatty liver disease (NAFLD) is a general term for a series of liver diseases ranging from hepatic steatosis alone (fatty liver) to non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis, and even hepatocellular carcinoma (HCC). Of these, hepatic steatosis alone (fatty liver) is known as NAFLD, and the occurrence of inflammation and liver cell damage is called NASH. Without effective intervention, the NASH may progress to cirrhosis. In the absence of alcohol or a small amount of alcohol, there is steatosis in more than 5% of liver cells, often combined with IR, metabolic syndrome (MetS), or type 2 diabetes mellitus (T2DM), and genetic variants of PNPLA3 or TM6SF2. The mechanisms are not fully understood but are involved in hepatic lipid accumulation, imbalance in energy metabolism, and inflammatory responses from various cell types. Lipid toxins, mitochondrial function, cytokines, and adipocytokines play major roles in a process of the disease. People with NAFLD often have insulin resistance, and a large number of T2DM patients develop NAFLD and its inflammatory complication NASH. The high incidence of NASH in patients with T2DM further leads to widely recognized complications such as cirrhosis and HCC. There are no clear clinical criteria for the diagnosis of NAFLD due to the naming of an exclusive diagnosis and the emphasis on alcohol consumption, and ignoring the metabolic causes and heterogeneity of NAFLD. Therefore, in March 2020, an expert consensus from an international team consisting of 30 experts in 22 countries recommended changing the name of NAFLD to metabolic dysfunction-associated fatty liver disease (MAFLD) [1]. MAFLD is based on histological (liver biopsy), imaging, and blood biomarker to show the evidence of liver fat accumulation (hepatic steatosis), with one of the following three conditions: overweight/obesity, T2DM, and metabolic dysfunction. The prevalence of MAFLD is up to 25%, which poses a serious threat to human health and imposes a huge economic burden on society, and so far in the United States and the European Union, no drugs have been approved to treat this disease. Under the absence of proven and effective therapies, we must combine the etiology of NAFLD and its underlying pathological risk factors to explore therapeutic strategies.
2. Epidemiology
At present, the pathogenesis and potential pathological risk factors of NAFLD have not been concluded. The definition of NAFLD is also disputed, and these uncertainties prevent the large-scale diagnostic screening of NAFLD. However, the incidence of NAFLD is increasing year by year, and the age of onset is also decreasing through the Healthy People Census and related research reports. With the rapid change of lifestyle, the incidence of NAFLD is increasing year by year, and it has developed into a major global public health crisis. According to statistics, the prevalence of NAFLD is about 25% globally. The prevalence of NAFLD is approximately 24% in the North American general population, 32% in South America, 23.7% in the EU, and 27.4% in Asia [2]. In the past 10 years, the cases of fatty liver in China have jumped from 18% to 29.2%, and middle-aged men have become a high-risk population [3]. The incidence of NAFLD has increased with a rise in obesity, T2DM, and MetS, and according to 2016 statistics, the NAFLD patients in China are predicted to rise from 246 million to 315 million in 2030. Thus, if not controlled, the NAFLD will be one of the leading cause of cirrhosis requiring liver transplantation during the next decade. While the incline in the prevalence of NASH is from 2% to 3%, NASH has been recognized as the main cause of HCC and one of the indications for liver transplantation (LT) in the United States.
3. Etiology
Based on the pathogenesis, NAFLD can be divided into two types: primary and secondary [4]. Insulin resistance is related to genetic susceptibility, excessive weight gain, and overweight caused by excess nutrition, MetS-related fatty liver such as obesity, diabetes, hyperlipidemia, and cryptogenic fatty liver are all the primary causes. NAFLD caused by malnutrition, total parenteral nutrition, rapid weight loss after bariatric surgery, drug/environmental, industrial poisoning, etc. belong to the category of secondary group.
However, the new definition of MAFLD points out that hepatic steatosis is secondary, and should avoid using the terms “primary” and “secondary” fatty liver to describe. The previous dichotomous classification (simple fatty liver and NAFLD) was replaced by activity and fibrosis to better describe the process of MAFLD [1].
4. Risk factors
NAFLD is closely related to environmental and genetic risk factors, such as obesity, T2DM, MetS, lifestyle, genetic factors, and so on. It should be noted that lifestyle changes are strongly associated with the incidence of NAFLD.
4.1 Obesity
Obesity is recognized as an independent risk factor for NAFLD. The World Health Organization (WHO) defines normal as body mass index (BMI) 18.5 < BMI < 24.9, while it is defined as 18.5 < BMI < 23.9 in China. BMI has been the most useful population-level measurement for defining overweight and obesity, with equal or over 25 being overweight and equal or over 30 being obese. And the measurement applies to all adults of all ages. The Report on Nutrition and Chronic Disease Status of Chinese Residents (2020), which conducted a field investigation of more than 600,000 among nearly 600 million people in 31 provinces (autonomous regions and municipalities) across the country, found that more than half of the adult residents were overweight or obese. The overweight and obesity rates of children and adolescents aged 6–17 years old and under the age of 6 were 19% and 10.4%, respectively.
However, BMI neither reflects the distribution of body composition and fat, nor distinguishes between visceral fat and subcutaneous fat. For example, because muscle density is greater than fat, BMI will overestimate the degree of obesity in people with high muscle mass and underestimate the degree of obesity in people with high-fat contents. Therefore, although within the same BMI range, great differences exist in cardiovascular risk and mortality among individuals. Some overweight and obese people have normal metabolism and do not develop T2DM or dyslipidemia, and other metabolic diseases, which are known as metabolically healthy obesity [5]. On the contrary, part of the populations with normal weight has a variety of cardiovascular risk factors, which are prone to metabolic diseases such as T2DM, high blood pressure (HBP), and dyslipidemia.
Metabolic abnormalities are closely related to adipose tissue, mainly manifested as increased abdominal visceral fat [6]. Abdominal visceral fat is the deep adipose tissue wrapped by fascia, accounting for about 20% of the total fat mass in men and 5–8% in women. Compared with subcutaneous fat (SAT), abdominal visceral fat is more closely related to endothelial dysfunction. Glucose transporter-4 is highly expressed in abdominal visceral adipocytes, enhancing the rate of glucose uptake [7]. In addition, abdominal visceral fat is rich in β1, β2 adrenergic receptors, and unique β3 adrenergic receptors required for fat metabolism, so fats are broken down rapidly, producing more free fatty acids (FFA) and glycerol [8, 9]. FFA directly enters the liver through the portal vein, and excessive FFA deposition leads to the inhibition of hepatic glucose utilization, resulting in hepatic IR [10]. The increased oxidation of FFA in peripheral muscles will reduce the oxidative utilization of glucose in peripheral tissues, resulting in IR in peripheral tissues. The release of FFA into the blood will synthesize TG, resulting in TG deposition in many non-adipose tissues and organs.
Because of genetic background, lifestyle, and other reasons, Asian people show the characteristics of a thin body, less muscle content, and easy accumulation of abdominal fat. Under the same weight, they are more likely to develop a cardiovascular disease such as IR and glucose and lipid metabolism disorders than Caucasians. IR is the pathogenesis and core link of the normal-weight metabolic obesity [11]. Insulin can lower blood sugar mainly by inhibiting hepatic glucose production, stimulating the uptake of glucose by visceral tissues (such as the liver), and promoting the utilization of glucose by peripheral tissues (skeletal muscle, fat). IR refers to the decreased sensitivity of the target organs of insulin action (mainly liver, muscle, and adipose tissue) to the insulin action [12].
4.2 Type 2 diabetes mellitus
T2DM is characterized by relative insulin deficiency caused by pancreatic β-cell dysfunction and IR in target organs [13]. Globally, obesity, sedentary lifestyles, and aging populations have led to a marked increase in the incidence and prevalence of T2DM in recent years. As the sixth leading cause of disability in 2015, diabetes imposes considerable socioeconomic pressure on the public and significant costs on the global health economy. Long-term high blood glucose, large blood vessels, and micro blood vessels are damaged and endanger the heart, brain, kidneys, peripheral nerves, eyes, feet, and so on. According to the statistics of WHO, there are more than 100 complications related to diabetes. More than half of the deaths from diabetes are caused by cardiovascular and cerebrovascular diseases, and 10% are caused by nephropathy [14]. Amputations due to diabetes are 10–20 times as many as non-diabetic patients with diabetes. The mechanisms of microvascular and macrovascular complications caused by hyperglycemia are endothelial dysfunction, formation of advanced glycation end products, hypercoagulability, increased platelet reactivity, and high expression of sodium-glucose cotransporter-2 (SGLT-2) [15]. In addition, isolated postprandial hyperglycemia is more common in Asian diabetic patients. Unlike obese T2DM insulin resistance mechanisms, Asian non-obese T2DM had higher visceral fat. Although the BMI of Asian T2DM patients is lower than that of European and American T2DM patients, the visceral fat of Asian T2DM patients is higher than that of European and American T2DM patients. It has been studied that higher visceral fat is related to insulin resistance, which may be related to the lipolysis of visceral fat being higher than that of the subcutaneous fat [16]. The decomposed free fatty acids enter the liver through the hepatic portal vein, which increases triglycerides in liver cells and leads to insulin resistance. Defective β-cell function plays a key role in the pathogenesis of T2DM. In the presence of insulin resistance, if β cells can compensate by increasing insulin secretion, the body can maintain normal blood sugar; when the function of β cells cannot compensate for insulin resistance, T2DM occurs. IR results in increased lipolysis and ultimately more free fatty acids entering the liver. Reduced glycogen synthesis and increased gluconeogenesis in the liver are the main features of IR. In diabetic patients, abnormal lipid metabolism will easily lead to fatty liver, which in turn affects blood sugar control, resulting in a vicious circle, overall, fatty liver compromises the ability of hypoglycemic drugs to control blood glucose. IR is not only an important mechanism for the pathogenesis of diabetes but also attracts more and more attention to the central link of the pathogenesis of NAFLD. Previous studies have shown that fatty liver in diabetic patients is more likely to develop NASH, liver fibrosis, and cirrhosis than in non-diabetic patients. People with diabetes have a higher risk of developing fibrosis than non-diabetic individuals [17]. Currently, the histopathological biopsy is the only effective way to determine the presence and severity of NASH [18]. However, due to the limited understanding of NAFLD, NASH diagnosis in T2DM is often missed or diagnosed too late, resulting in the occurrence of end-stage liver diseases and serious consequences caused by metabolic disorders, such as cardiovascular and cerebrovascular diseases. The survival rates of patients also decline, while the medical cost will rise.
4.3 Metabolic syndrome
Metabolic syndrome (MetS) may have multiple causes, ranging from a set of unrelated risk factors to the series of risk factors linked by common underlying mechanisms [19]. Previously, MetS is often used as part of an overall risk assessment for cardiovascular disease. The diagnosis is based on abdominal obesity (highly associated with IR), decreased high-density lipoprotein cholesterol (HDL-C), elevated blood pressure, triglycerides, and fasting glucose (IFG or T2DM) [20]. The diagnostic criteria of the Diabetes Society of the Chinese Medical Association for MetS are adopted in China, and those who meet three or more criteria are MetS: a. BMI ≥ 25 kg/m2; b. TG ≥ 1.7 mmoL and/or HDLC < 0.9 mmoL (male) or HDLC < 1.0mmo/L (female); c. SBP ≥ 140 mmHg and/or DBP ≥ 90 mmHg (1 mmHg = 0.1333 kPa) and/or diagnosed with hypertension and treated; d. FBG ≥ 6.1mmo and/or diagnosed with diabetic patients. NAFLD is considered as a hepatic manifestation of MetS. The liver, as a key organ of systemic metabolism, in turn, affects the risk of MetS and its complications. Increasing pieces of evidence show that the relationship between NAFLD and MetS are bidirectional [21]. These two clinicopathological syndromes share many aspects of their pathophysiology and IR is at the core of both. IR and MetS can exacerbate liver disease. Several cross-sectional studies have indicated that MetS and its components are associated with an increased risk of NAFLD in various populations compared with individuals without MetS.
4.4 Lifestyle
Rapid urbanization and lifestyle changes are associated with an increased incidence of NAFLD. Urbanization has led to an accelerated pace of life, dietary imbalances, such as irregular diets and high intake of saturated fat, carbohydrates, and trans-fatty acids, which are associated with IR and dyslipidemia. In addition, a sedentary lifestyle is also an important factor in NAFLD [22]. The fast-paced life and convenient transportation in cities make people less and less physically active in their daily and spare time. Age, increased smoking and alcohol consumption, screen time, decreased sleep, education, and stress all amplify the effects of IR and abdominal obesity, further increasing the prevalence of NAFLD.
4.5 Genetic factors
In addition to IR and MetS, genetic factors also play an important role in the occurrence and development of NAFLD. The human pastatin-like phospholipase domain containing 3 (PNPLA3) gene encodes 481 amino acid proteins called adiponutrin [23]. The exact role of this protein is still unknown, but it is thought to be a membrane-associated protein expressed in liver and adipose tissue, with lipogenic and lipolytic activities. It has been documented that it is located in lipid droplets (LDs) and may play a role in triglyceride hydrolysis. The gene is located in the long arm of chromosome 22. The variant rs738409 is the result of the substitution of cytosine by guanine, encoding isoleucine replaced by methionine at position 148 (I148M) of the protein. Substantial shreds of evidence suggest that this polymorphism is the strongest genetic determinant across the entire NAFLD lineage [23].
According to a study on the association of NAFLD among the medical patients in Uyghur and Beijing, it was found that the genotype frequency of PNPLA3-rs738409CG and GG genotype in NAFLD patients was higher than that in healthy controls, and the frequency of PNPLA3-rs738409G allele in NAFLD patients was higher than that in healthy controls [24, 25]. At the same time, the univariate logistic regression analysis of the genotype distribution of PNPLA3-rs738409 and NAFLD showed that compared with the PNPLA3-rs738409CC genotype, the GG genotype had a higher risk of NAFLD. Down-regulation of PNPLA3 mutant proteins will have beneficial effects on NAFLD and maybe a new therapeutic target for NAFLD treatment.
A similar situation was found in the transmembrane 6 superfamily member 2 (TM6SF2) gene. TM6SF2 is also present in LDs and mainly expressed in the liver and gut. It is believed as a key regulator of hepatic fat metabolism and secreting triglyceride-rich lipoproteins. The variant, identified as E167K, or rs58542926, is unrelated to NPLA3 variants but associated with susceptibility to NAFLD, and with advanced fibrosis and cirrhosis [26].
4.6 Gut flora
The influence of gut bacteria on liver homeostasis is based on an anatomical basis between the gastrointestinal tract and the liver, commonly referred to as the “gut-liver axis” [27]. The liver transports bile acids and antibacterial molecules (primary bile acids, IgA, and angiopoietin) to the intestinal lumen via the bile duct to control bacterial overgrowth and maintain intestinal flora balance. Liver products (bile acids) influence gut microbiota composition and barrier integrity. Under normal circumstances, intestinal mucosal epithelial cells, intercellular tight junctions, and biofilm constitute the mechanical barrier of the intestinal tract, which can effectively prevent harmful substances such as bacteria and endotoxins from entering the blood through the intestinal mucosa. Pathologically, microbiota-dysbiotic bacteria and their derivatives translocate to the liver through a disrupted gut barrier, where they cause hepatic inflammatory responses and commensal or metabolite-induced interactions that induce steatosis. In addition, there is increasing evidence that patients with NAFLD also have gut barrier dysfunction or altered gut permeability. Although the causal relationship between NAFLD/NASH co-occurrence and disruption of the gut epithelial barrier is unclear, impaired gut permeability exacerbates NASH [28].
5. Pathophysiology and pathogenesis
5.1 Theoretical hypothesis of “two-hit” and “multiple hit” in NAFLD
The pathogenesis of NAFLD is complex and still not fully clarified, and its pathogenesis was initially dominated by the“two-hit” hypothesis [29]. Hepatic steatosis is the first step in the development of NAFLD. A high energy intake from dietary fat, a marginal decrease in fatty acid oxidation, and an increase in hepatic lipid synthesis can all contribute to the abnormal accumulation of lipids in hepatocytes (the first hit). This process is associated with IR, which leads to dysfunction of intracellular triglyceride synthesis and transport. The “second hit” is based on the fact that lipid metabolism dysfunction and mitochondrial dysfunction occur in the liver, triggering inflammation and oxidative stress caused by fatty acid peroxidation mediated by cytokines, inflammatory factors, and endotoxins. These factors can trigger a series of signaling pathways, activate liver Kupffer cells, hepatic stellate cells (HSCs), immune cells, etc., and cause pathological changes in liver tissue such as inflammation, steatosis, and liver fibrosis to form NAFLD.
In recent years, as the public pays more and more attention to NAFLD, and the research on NAFLD continues to deepen and improve, the complexity of the pathogenesis of NAFLD is far more than the “two-hit” hypothesis, and the “multiple hit” hypothesis has emerged to explain it. The “multiple hit” hypothesis suggests that the progression of NAFLD involves the occurrence of “parallel, multiple” injuries [30]. Oxidative stress, lipid peroxidation, and IR, mitochondrial dysfunction, dysregulation of cytokines, activation of HSCs, and gut-derived bacterial endotoxemia caused by intestinal flora disturbance, as well as dietary habits, environmental factors, and genetic factors are in the occurrence and development of NAFLD play a role at the same time.
5.2 Insulin resistance
Insulin is a protein hormone secreted by pancreatic islet beta cells stimulated by endogenous or exogenous substances such as glucose and glucagon. The biological action of insulin at the cellular level is initiated by binding to specific receptors on the target cell membrane [31]. Insulin receptors are membrane glycoproteins composed of two separate insulin-binding domains (alpha subunits) and two signaling domains (beta subunits). The binding of insulin to the receptor causes conformational changes in α-subunit, so that adenosine triphosphate (ATP) can bind to the intracellular domain of β-subunit. After binding to ATP, the tyrosine kinase in the β- subunit is activated, which in turn auto-phosphorylates the insulin receptor [32]. Insulin mainly acts on the liver, muscle, and adipose tissue, and controls the metabolism and storage of the three major nutrients, protein, sugar, and fat. Normally, insulin reduces glucose production by reducing hepatic gluconeogenesis and glycogenolysis, accelerates glucose uptake by adipose and skeletal muscle tissue, regulates glucose homeostasis, and prevents the conversion of excess glucose to lipid deposition. Systemic or local IR occurs when the sensitivity and responsiveness of insulin target organs or tissues to endogenous or exogenous insulin are reduced. In a sense, IR is a compensatory response mechanism of the body to excess energy. Eating a lot of carbohydrates can cause our body to store more glycogen, which leads to the continuous release of insulin, the body’s sensitivity to insulin slowly decreases over time, until eventually, maybe due to impaired insulin secretion, resistance to peripheral actions of insulin, or both. In IR, on the one hand, insulin cannot effectively promote glycogen synthesis, it specifically reduces hepatic gluconeogenesis and rapidly lowers blood sugar. On the other hand, it is the effect of lipid synthesis in the liver that leads to hyperglycemia and hypertriglyceridemia that greatly affects the metabolic balance of the body. IR in the liver is often associated with T2DM, MetS, and NAFLD [33].
5.3 Lipotoxicity
Adipose tissues play a central role in body metabolism by regulating fatty acid synthesis, release, and glucose utilization, maintaining the balance of skeletal muscle and liver metabolism. Therefore, fat accumulation is not only associated with obesity but also causes fat-related metabolic disorders, among which obesity-related IR is an important way to affect the body’s energy stability. The original concept of lipotoxicity refers to the effect of excess FFA on the secretory function of pancreatic islet B cells under high-fat diet conditions [34]. With the deepening of research, it has been found that excessive lipid deposition in non-adipose tissues such as skeletal muscle, cardiac muscle, and liver can lead to cell dysfunction or cell death. Ectopic fat deposition leads to metabolic disorders of the corresponding organ, thus expanding the understanding of lipotoxicity. It is generally believed that excess intake of carbohydrates or fat gets stored in subcutaneous fat and visceral fat. When the storage capacity of adipose tissue is exceeded, especially in obese individuals, triglyceride from adipose tissue can be broken down to glycerol and FFA, and FFA can be mobilized by binding to plasma albumin. The FFA level in peripheral blood increases, an imbalance occurs in the uptake and metabolism of fatty acids. The utilization of FFA is hindered, resulting in insufficient lipid oxidation, thereby causing a large number of lipids and their products to accumulate in various tissues and organs. Inadequately oxidized lipids are stored in liver fat droplets in the form of triglycerides. Steatosis of the liver or fatty liver occurs when the accumulation of LDs in hepatocytes exceeds the storage and oxidative capacity of the liver. Steatosis of a large number of hepatocytes can induce liver dysfunction, including lipid accumulation and oxidative stress caused by lipid metabolites, inflammation, apoptosis, and liver fibrosis. This pathological process is called lipotoxicity. The failure of hepatocytes to deal with excess FFA-induced lipotoxicity promotes ER and oxidative stress leading to apoptosis, which is also a major feature of the NAFLD [28].
5.4 Endoplasmic reticulum stress
The endoplasmic reticulum (ER) is an organelle mainly responsible for physiological functions such as protein and lipid metabolism in eukaryotic cells. The membrane within the cytoplasm forms a series of sheet-like sacs and tubular lumens that communicate with each other to form a conduit system isolated from the cellular matrix. Because the conduit system is close to the inner side of the cytoplasm, it is called the endoplasmic reticulum. The ER is an important organelle related to metabolism. It has a sophisticated and complex control system to participate in intracellular anabolism and catabolism, such as protein synthesis and degradation, glycogen synthesis and decomposition, membrane lipid synthesis and recovery, fat storage, and hormone metabolism (such as production and secretion of insulin, leptin, resistin, etc.), and so on [35]. The ER is also a nutrient sensor in the body. Hyperglycemia, hyperlipidemia, and more inflammatory factors secreted by adipose tissue that accompany obesity are all stress signals of the ER. A long-term high-fat diet will increase blood sugar and fatty acids and induce disorder of glucose and lipid metabolism. Excessive high-sugar and high-fat substances entering cells for anabolism will increase the burden on the ER, increasing unfolded or misfolded proteins. When the accumulation of a large number of unfolded proteins exceeds a certain level, the corresponding unfolded protein response (UPR)-related signaling pathways are activated, resulting in an imbalance of ER function homeostasis. This state of homeostatic imbalance is called ER stress. The URP pathway is highly conserved and mainly mediated by three ER transmembrane proteins: pancreatic endoplasmic reticulum kinase (PERK), inositol-requiring enzyme 1α (IRE1α), and activating transcription factor (ATF6) [36]. It is generally believed that these three proteins all have domain located in the lumen of the ER, which can sense the concentration of misfolded proteins in the lumen. Under normal circumstances, ER stress inhibits the synthesis of nascent proteins, promotes the correct folding of unfolded proteins, and accelerates the degradation of misfolded proteins through its associated unfolded protein response (UPR) signaling pathway, thus exerting a protective effect on cells. However, once the UPR is activated excessively or persistently by ER stress, the endoplasmic reticulum-induced apoptosis pathway will be triggered, resulting in apoptosis. ER stress can also inhibit insulin signaling by activating UPR-corresponding kinases, such as IRE1α, phosphorylation of JNK, and IkB kinases [37]. In addition, related studies have also shown that FFAs-induced lipotoxicity also promotes ER stress and oxidative stress. CHOP (C/EBP-homologous protein), also known as GADD153 (growth arrest and DNA damage-inducible protein) or DDIT3 (DNA-damage inducible transcription 3). CHOP is considered a proapoptotic marker of ER stress-dependent cell death.
Elevated expression of the ER stress marker CHOP was detected in liver biopsies from patients with NAFLD [38], suggesting that ER stress-induced apoptosis in hepatocytes is likely related to the progression from steatosis to NAFLD in humans.
5.5 Inflammation
Although the pathogenesis of NAFLD has not been fully elucidated, the inflammatory response runs through the entire pathological process of NAFLD. In NAFLD patients, showing the increase of FFA released into the blood circulation and the decrease of the oxygen content of adipocytes, both act together to induce the activation of hypoxia-inducible factor (HIF1) and downstream target genes in adipocytes, and ER stress [39], resulting in cell death and specific inflammatory response. The inflammatory markers tumor necrosis factor-alpha (TNF-α), interleukin 6 (IL-6), and C-reactive protein (CRP) in NAFLD patients were significantly higher than those in healthy people [40]. TNF-α is secreted by macrophages and increases with the content of adipose tissues in the body. Highly expressed TNF-α induces phosphorylation and inactivation of insulin receptors in adipose tissues and smooth muscle cells, increases lipolysis to generate FFA, and inhibits adiponectin release. IL-6 is a cytokine produced by adipocytes and immune cells and has a complex regulatory mechanism in the body. The IL-6 production increases with the increased body fat and IR. It acts on the liver, bone marrow, and endothelium, increasing the expression of the acute phase reactant CRP in the liver. Several studies have shown a correlation between high CRP levels and the development of NAFLD as well [41]. Increased production and release of pro-inflammatory factors (TNF-α, IL-6, and CRP) can induce IR in the liver, skeletal muscle, and adipose tissue through insulin-interfering signaling pathways.
Therefore, inflammation and metabolic changes in adipose tissues can also trigger NAFLD.
5.6 Leptin and adiponectin
Adipokines also play an important role in the process of NAFLD-related liver fibrosis. Leptin is a hormone secreted by adipose tissue that can promote fibrosis [42]. The content of leptin in serum is positively correlated with the content of adipose tissue in the body. Normally, leptin functions primarily as an afferent signal in a feedback loop, acting on neurons in the hypothalamus to regulate feeding and other physiological functions. The researchers found that the level of leptin in the blood circulation increases when the body undergoes an inflammatory response, and many acute-phase factors, such as TNF-α, IL-1, IL-6, and bacterial lipopolysaccharide (LPS) stimulation, can rapidly increase leptin levels [43]. Leptin can also alter insulin action, induce angiogenesis, reduce endothelial NO synthase, and interact with the immune system [44]. In addition, leptin can activate HSCs by activating the JAK/STAT pathway. HSCs are the main source of extracellular matrix in liver fibrosis [45].
Adiponectin (ADPN) is also a protein hormone mainly secreted by adipocytes. ADPN mainly exists in blood circulation and plays an important role in the regulation of insulin sensitivity and glucose metabolism. ADPN reduces the level of plasma-free fatty acid (FFAs) by promoting fatty acid oxidation. There are two types of adiponectin receptors, adiponectin receptor 1 (AdipoR1) which is mainly distributed in skeletal muscle, and adiponectin receptor 2 (AdipoR2) which is abundantly expressed in the liver. Studies in mammals have shown that ADPN activates the adenylate-activated protein kinase (AMPK) signaling pathway through AdipoR1 and AdipoR2 [46]. Activated AMPK induces phosphorylation inactivation of acetyl-CoA carboxylase (ACC), thereby promoting fatty acid oxidation. In addition, peroxisome proliferator-activated receptor alpha (PPAR-α) is a key transcription factor regulating lipid metabolism in animals. As a downstream factor of the AMPK signaling pathway, it is also involved in the effect of ADPN on enhancing fatty acid oxidation [47]. Studies have shown that highly expressed ADPN attenuates the proliferation and migration of HSCs and promotes apoptosis of HSCs by inducing the expression of nitric oxide synthase (iNOS) and messenger RNA (mRNA) in HSCs, which hinders liver fibrosis [48]. In addition, blood ADPN concentrations are significantly reduced in MetS, diabetes, atherosclerosis, and NAFLD, in contrast to other cytokines, making ADPN a possible hallmark of these diseases.
5.7 Hepatic stellate cells
Hepatic stellate cells (HSCs) are a kind of non-parenchymal cells unique to the liver, accounting for about 8–13% of the total number of liver cells. HSCs have a dual phenotype of quiescence and activation [49]. In normal liver, the cells are quiescent. At this time, the cells act as hepatic fat-storing cells, and the intracellular LDs are abundant. The autofluorescence properties of vitamin-A stored in the LDs under the microscope contribute to the localization of the cells. During the development of NAFLD, multiple factors within the micro-circle promote the activation and transdifferentiation of HSCs into myofibroblasts. Activated HSCs can also massively secrete extracellular matrix (ECM), tissue inhibitors of metalloproteinases (TIMPS), matrix metalloproteinases (MMPs), and α-smooth muscle actin (α-SMA) [50]. The continuous activation of HSCs is a key link in the development and progression of liver fibrosis. On the one hand, HSCs produce 80% of type I collagen in fibrotic tissue, which induces liver remodeling. On the other hand, intra-hepatic sinusoidal pressure is increased by cell contraction. These two types of changes finally laid the pathological basis of NAFLD-related liver fibrosis. Existing studies have found that in the mechanism of liver fibrosis, growth factor signaling has a significant role in the activation of HSCs. Growth factors such as transforming growth factor (TGF)-α, epidermal growth factor (EGF), platelet-derived growth factor (PDGF), and other growth factors activate HSCs through signaling, promoting ECM remodeling, leading to collagen formation [51]. The molecular pathways of HSCs activation are complex and involve a variety of signaling pathways. The characteristics of HSCs and their roles in the repair of hepatocyte injury and local immunity in the liver still require more in-depth research.
6. Clinical manifestations
The onset of NAFLD is insidious, slow onset, and often asymptomatic. A small number of patients may have non-specific symptoms such as fatigue, mild discomfort in the right upper quadrant, dull pain in the liver area, or upper abdominal distension. With the development of the disease, some NAFLD patients may have symptoms such as jaundice, anorexia, nausea, and vomiting, which may be accompanied by hepatomegaly. In the decompensated stage of NAFLD-related liver cirrhosis, the clinical manifestations are similar to those of liver cirrhosis caused by other causes.
7. Diagnosis
NAFLD represents the liver manifestation of a multi-system disease, with heterogeneity in underlying causes, presentation, course, and outcomes. NAFLD means that the whole body is in a state of metabolic dysfunction.
Liver biopsy is considered to be the gold standard for defining NAFLD and able to distinguish steatosis from NASH. However, it is not recommended routinely because of the increased risk of bleeding and complications. Ultrasound is the most recommended and widely used diagnostic method for the identification of hepatic steatosis due to its sensitivity and non-invasiveness.
Over the past few decades, several expert groups have attempted to develop simple diagnostic criteria for clinical practice to identify NAFLD patients. The latest expert consensus in 2020 clarifies that the diagnosis of MAFLD is mainly based on histology, imaging, or blood biomarker evidence of the presence of fat accumulation in the liver (hepatic steatosis), in addition to one of three criteria (i.e., overweight/obesity, presence of T2DM or evidence of metabolic dysregulation) [1]. The presence of at least two metabolic risk abnormalities may correctly diagnose NAFLD in non-overweight/obese individuals.
8. Differential diagnosis
8.1 Alcoholic liver disease
Before the name of NAFLD was suggested to be changed to MAFLD, the difference between NAFLD and alcoholic liver disease (ALD) is mainly based on the prescribed amount and duration of drinking. Drinking history is a prerequisite for the diagnosis of ALD [52]. If there is no history of drinking, the diagnosis of ALD does not need to be considered. However, if the patient has a history of excessive drinking but the duration is less than 5 years or more than 5 years but the average drinking amount does not exceed the standard, this means that part of the population falls between the two diagnostic criteria when it comes to drinking.
After ethanol enters hepatocytes, it is oxidized by hepatic alcohol dehydrogenase, catalase, and hepatic microsomal alcohol oxidase, and finally forming acetaldehyde. Acetaldehyde has strong lipid peroxidation, and obvious toxic and side effects on hepatocytes, which hinders their metabolism and leads to degeneration and necrosis of hepatocytes. In addition, ethanol can affect the occurrence and development of liver disease by regulating intestinal flora, inflammatory response, and fibrosis [53]. Compared with NAFLD, patients with ALD have obvious liver disease presentation and rapid disease progression, and a higher risk of liver cirrhosis, liver failure, or liver cancer.
At present, a few studies have focused on the differential diagnosis of NAFLD and ALD, and many studies used non-fatty liver patients or healthy people as controls. There are still many problems and unknown factors in the differential diagnosis of NAFLD and alcoholic liver disease. Clinically, ALD is more likely to be diagnosed when there are obvious clinical manifestations of chronic hepatitis and cirrhosis, especially extrahepatic and neuropsychiatric manifestations. While NAFLD is more likely to be diagnosed when there are mild or even no symptoms. For the patients who drank alcohol, the changes of indicators within 4 weeks after abstinence were helpful for the differential diagnosis of NAFLD and ALD.
8.2 Chronic viral hepatitis
Viral hepatitis, as an infectious disease, is mainly caused by a variety of hepatitis viruses. There are five recognized types of viral hepatitis, namely hepatitis A virus (HAV), hepatitis B virus (HBV), hepatitis C virus (HCV), hepatitis D virus (HDV), and hepatitis E virus (HEV). All viral hepatitis is contagious, but the route of transmission and the intensity of infection vary. Hepatitis A and E are acute hepatitis, and types B, C, and D, are chronic hepatitis and can develop liver cirrhosis and HCC. Hepatitis D virus can only be transmitted in individuals with the presence of hepatitis B virus, so normal people do not get hepatitis D. Chronic viral hepatitis is an inflammation of the liver caused by the hepatitis virus that lasts for more than 6 months. The hepatitis virus usually causes symptoms after it has severely damaged the liver [54]. Viral hepatitis is an infectious disease with the highest infection rate and the greatest harm to patients in China.
HBV is an enveloped partially double-stranded DNA virus, consisting of an outer lipid envelope embedded with hepatitis B surface antigen (HBsAg) and a nucleocapsid containing hepatitis B core antigen (HBcAg), viral polymerase, and DNA genome. Clinically, it is difficult to distinguish hepatitis B from hepatitis caused by other viral agents, and the diagnosis must be confirmed by laboratory tests. The laboratory tests for hepatitis B surface antigen (HBsAg) are used to diagnose hepatitis B infection. Acute HBV infection is characterized by the presence of hepatitis B surface antigen-antibody and immunoglobulin IgM type anti-core antigen-antibody. In the early stage of infection, the serum of patients can also be positive for hepatitis B-e antigen (HBeAg). Chronic infection is characterized by the persistence of HBsAg-antibodies (with or without HBeAg positivity) (>6 months). The persistence of HBsAg-antibodies is a primary risk marker for the development of chronic liver disease and progression to HCC. The presence of HBeAg positivity indicates that the blood and body fluids of infected individuals are highly contagious [55].
HCV is a single-stranded RNA virus that can be divided into six genotypes and several subtypes. The genome of HCV encodes a single polyprotein that can be translated and processed into structural and nonstructural proteins. And the nonstructural proteins have key functions in viral replication. During the acute phase of HCV infection, the presence of an HCV-specific CD4-T cells response is associated with the control of viral replication. If the response of the CD4-T cell is sustained and maintained, HCV is permanently eliminated. If the CD4-T cells’ response is lost, rebound viral replication or viremia occurs, resulting in a viral persistence [56]. In chronic HCV infection, CD4-T cells are functionally limited due to impaired proliferative capacity, which is caused by HCV core-mediated inhibition of IL-2 secretion.
8.3 Autoimmune liver diseases
Autoimmune liver diseases (ALDs) refer to a group of non-infectious liver diseases characterized by liver pathological damage and abnormal liver function. Its pathogenesis may be related to autoimmunity, mainly including autoimmune hepatitis (AIH), primary biliary cirrhosis (PBC), primary sclerosing cholangitis (PSC), and any overlapping syndrome of these three diseases. AIH is mainly causing damage to liver cells, while PBC and PSC are mainly damaging the biliary tract. The main damage is related to abnormal autoimmune function. ALDs are chronic diseases with a long natural history and progressive development, which eventually leads to liver cirrhosis and liver failure [57]. China still lacks exact statistics, but the number of clinically detected and reported cases has significantly increased in recent years. At present, it is believed that ALDs are caused by the breakdown of the immune system’s immune tolerance to self-antigens, which induces an immune attack on the liver. Genetic susceptibility and environmental factors are the initiating factors, and the pathogenesis may be related to factors such as infection, chemical factors, cytokine networks, and molecular mimicry of self-antigens. However, the specific etiology and pathogenesis are still unclear, and there is currently no single clinical or laboratory index to diagnose ALDs. It is necessary to comprehensively integrate clinical manifestations, laboratory examinations, and liver histological characteristics to exclude other possible causes of chronic hepatitis. Clinically, patients with ALDs lack specificity. Initially, symptoms such as fatigue, pruritus, jaundice, and abdominal pain are often present. Biochemical tests are often abnormal in liver function. The presence of autoantibodies in serum is an important feature for diagnosis and differential diagnosis, such as ANA, SMA, AMAM2, etc., and histopathological examination of the liver is also very important [58].
8.4 Hepatolenticular degeneration
Hepatolenticular degeneration, also known as Wilson disease (WD), is an autosomal recessive genetic disorder caused by the mutation of the ATPase copper transport β gene ATP7B, resulting in disturbance of copper metabolism in the body [59]. The genetic mutations lead to the defective or loss of ATPase function, resulting in the obstruction of copper excretion in the bile duct, and a large amount of copper accumulates in the brain, liver, kidney, bone, joint, cornea, and other tissues or organs. The carrier frequency and prevalence rate of this disease in the world are 1:100–1:90, and 1:40,000–1:30,000 respectively. Clinically, the clinical manifestations of WD patients are diverse, and the clinical manifestations can be mainly divided into brain type, liver type, mixed type, and other types. The manifestations of cerebral-type patients mainly include Parkinson’s syndrome, dyskinesia, oral and mandibular dystonia, and psychiatric symptoms. The main clinical symptoms of liver patients include asymptomatic elevation of transhelicase, hepatomegaly, splenomegaly, hepatitis, fatty liver, cirrhosis, and acute liver failure. Excessive copper will also be deposited in the kidneys, bones and joints, blood, skin, cornea, and other tissues or organs, causing corresponding tissue and organ damage. Since the human body’s copper is mainly excreted from the liver in the form of bile, many liver diseases themselves can lead to abnormal copper metabolism indicators in the human body. Therefore, for patients with only liver involvement, the interpretation of auxiliary examination indicators needs to be more cautious, and a comprehensive evaluation should be combined with a variety of examination methods. The new 2021 health guidelines in China remind clinicians to be highly alert the individuals with serum ceruloplasmin <120 mg and children with elevated liver enzymes and 24 h urinary copper ≥40 μg. It is recommended to perform ATP7B gene testing to confirm the diagnosis.
Specific diseases, such as alcoholic liver disease, chronic viral hepatitis, autoimmune liver disease, and Wilson’s disease that can lead to fatty liver need to be excluded, as well as drugs (tamoxifen, amiodarone, methotrexate, glucocorticoids, etc.), total parenteral nutrition, inflammatory bowel disease, hypothyroidism, Cushing’s syndrome, lack of β-lipoproteinemia, and congenital IR syndrome-related fatty liver also need to be excluded.
9. Treatment
Generally, non-alcoholic fatty liver (NAFL) progresses relatively slowly. But when NAFL progresses to NASH without effective intervention, 15–25% of patients can progress to liver cirrhosis or even HCC within 10–15 years. Exploring and eliminating the causes are the fundamental ways to treat this disease. Obese people need to more effectively control their weight, and diabetic patients require effective treatment. People with malnutrition need to adjust to a balanced diet, and so on. The speed of weight loss is a key factor in determining the improvement or deterioration of liver histology.
9.1 Lifestyle
Because the etiology and pathogenesis of NAFLD are unknown, there is no effective drug therapy for liver disease. None of NASH drugs are currently in Phase III clinical trials, and there are no drugs approved by government regulators to treat NASH.
For obese patients with fatty liver, diet therapy is the basis and key approach. Lifestyle modification is recommended as the primary treatment for NAFLD [60]. For NAFLD patients who are overweight or obese (abdominal obesity), the first optional lifestyle is aimed at weight loss with a range of 8–10%. More than 50% of patients fail to meet the target and require individualized drug treatment. NAFLD patients should adjust their diet, which should be supplemented with high protein, an appropriate amount of fat, and sugar with rationally allocated. The total energy intake should be controlled at about 20–25 kcal per kilogram per day. Meanwhile, patients should strictly control their daily salt intake, avoid foods rich in monosaccharides and disaccharides, such as high-sugar pastries, ice cream, candies, etc.
Exercise is very important in the treatment of NAFLD. It is recommended that patients should take aerobic exercise, such as jogging, brisk walking, swimming, and so on. The specific time and amount of each and gradual exercise need to be personalized. Weight loss is generally controlled at 0.5–1 kg/week because losing weight too quickly is also harmful to the body.
9.2 Obesity management
Weight loss should be a priority in obese patients and those with MetS. Obesity can be addressed through lifestyle changes such as a low-calorie diet with an adequate intake of fruits and vegetables and increased physical activity. Although medical treatment and bariatric surgery may also be considered, however, the adverse effects cannot be eliminated.
9.3 Pharmacotherapy for patients with T2DM
NAFLD is an acquired metabolic stress-induced liver injury closely associated with IR and genetic susceptibility. The metabolic disorders in T2DM patients are similar to NAFLD. Therefore, the glucose metabolism in T2DM patients with NAFLD will further deteriorate, making diabetes difficult to control, and requiring more hypoglycemic drug treatment. Metformin is the preferred treatment for patients with T2DM unless there is a specific contraindication, such as in patients with renal impairment.
Since metformin does not promote insulin secretion, it generally does not cause hypoglycemia when used alone. Animal and in vitro studies have shown that metformin has a protective effect against several T2DM-related cardiovascular diseases, including myocardial infarction, hypertrophic, and diabetic cardiomyopathy, which lead to cardiac insufficiency and the potential progression to heart failure. The molecular mechanisms involved in this protection are multifaceted and function primarily by acting on vascular endothelial cells, cardiomyocytes, and fibroblasts. Since metformin is excreted by the kidney, the accumulation of metformin and lactic acid easily occurs in the body when the kidney functions insufficiently, increasing the risk of acidosis thereby. The doctors generally recommend cessation when the serum creatinine is greater than 150 micromol/liter. In addition, the drug should also be discontinued when there is severe cardiac and liver dysfunction, and the liver and kidney functions should be checked regularly during the medication.
Sulfonylureas, such as gliclazide and glimepiride, act on β cells to stimulate insulin secretion and increase the level of insulin in the body. Some sulfonylurea drugs (such as glimepiride) can enhance the sensitivity of peripheral tissues to insulin, reduce the output of hepatic glycogen, and also have the effect of reducing platelet aggregation, regulating blood lipids and blood viscosity, and improving blood circulation (e.g., gliclazide). Sulfonylureas boost the production of insulin, a hormone that promotes energy storage, which may indirectly contribute to weight gain. Among various sulfonylureas, clinical studies have shown that glipizide controlled-release tablets and glimepiride have no significant effect on weight gain. Metformin, acarbose, and sodium-glucose cotransporter 2 (SGLT-2) inhibitors also have weight loss effects. For overweight or obese patients, sulfonylureas in combination with these drugs may reduce the risk of weight gain associated with sulfonylureas.
NAFLD patients with diabetes should have effective improvement not only in NASH, but also in NAFLD-related MetS, T2DM, and cardiovascular diseases. In the treatment of NASH, it is necessary to take effective measures to lose 8–10% of body weight, including lifestyle intervention. If the standard is not met, drug treatment can be selected. Patients eligible for bariatric surgery may also be considered.
9.4 Gut flora
In addition to genetic susceptibility and diet, the gut microbiota influences hepatic carbohydrate, lipid metabolism, and the balance between pro-and anti-inflammatory cytokines in the liver, thereby affecting NAFLD and its progression to NASH. Hyperproliferation of intestinal bacteria can lead to changes in cytokines in the portal vein and liver, so probiotics and antibiotics may help treat this disease. Animal experiments have shown that probiotics can down-regulate TNF-α levels and reduce liver inflammation, but clinical studies are needed to confirm the efficacy. Antibiotics that are not absorbed in the gut may be helpful in the treatment of intestinal bacterial hyperproliferation. Rifaximin, which is rarely absorbed in the gut, is well tolerated and may have certain advantages [61]. However, there is no randomized controlled clinical study to observe the efficacy of antibiotics on NAFLD.
9.5 Potential drugs
Studies have found that liver fibrosis can be reversed in a series of processes including the occurrence and development of NAFLD. The activation of HSCs to produce collagen is the core link of liver fibrosis. Although great progress has been made in the study of HSCs activation-related genes, few breakthroughs are achieved in the treatment of liver fibrosis, and the search for effective anti-fibrosis drugs is still a research hotspot. By choosing appropriate drugs, the clinical prognosis of NAFLD can be optimal, which has important social and economic significance.
9.5.1 Curcumin
Turmeric is the dried rhizome of turmeric (Curcuma longa L.), which has been used in traditional medicine in China for thousands of years and is widely used in flavoring, dyeing, and pharmaceutical industries. The main active ingredient is a class of diarylheptane compounds derived from ginger plants, which mainly exist in the rhizomes of medicinal plants such as turmeric, tulip, and Curcuma. At present, more than 40 kinds of Curcumin compounds have been isolated from the genus Curcuma, among which Curcumin is the main active substance, and the main chain is unsaturated aliphatic and aromatic groups. Since it was first isolated from plants in 1870 but its molecular structure was determined in 1910, years of research have found that it has a variety of biological functions, such as regulating blood lipids, anti-tumor, anti-virus, and anti-inflammatory effects, and act as antioxidants. Through research on the mechanism and intervention of NAFLD-related hepatic stellate cell activation, it is of great theoretical significance to clarify the potential mechanism of Curcumin to inhibit the occurrence of hepatic fibrosis.
Liver fibrosis is a wound repair response to chronic liver injury (viral infection, alcoholism, cholestasis, etc.), and is a pathological process of excessive extracellular matrix (ECM) production and deposition. Chronic liver injury leads to the accumulation of a large number of inflammatory cells, which release inflammatory factors and growth factors, such as TNF-α and TGF-β1, thereby activating HSCs, which are generated by ECM (especially collagen fibers). Curcumin has received great attention as a dietary supplement for liver protection. Curcumin can inhibit the activities of lipoxygenase and cyclooxygenase-2 (COX-2), inhibit lipid peroxidation, reduce the release of arachidonic acid, especially the inflammatory factors ILs by inhibiting the NF-kB signaling pathway—production of 1β, IL-6, TNF-α. Our previous findings provide new insights into the mechanism of action of curcumin and a therapeutic candidate for the prevention and treatment of hyperleptinemia-induced liver fibrosis in NASH patients with obesity and/or T2DM [62, 63, 64]. In recent years, several in vitro and in vivo studies have also shown that curcumin can intervene in the pathological process of liver diseases from multiple links, and has anti-hepatic injury, anti-steatosis, anti-fibrosis, and anti-cancer effects. However, due to the poor water solubility and low bioavailability of curcumin, its clinical application is greatly limited. Therefore, the formulation and structural modification of curcumin as a lead compound are currently hot and crucial research topics.
9.5.2 Vitamin E
Vitamin E is a fat-soluble vitamin with antioxidant function, which is necessary for the normal growth and reproduction of animals. Studies have found that vitamin E has a similar biological activity to a-tocopherol, which can provide a hydrogen ion on the color ring to scavenge free radicals, thereby playing an anti-oxidative stress role. In addition to scavenging reactive oxygen free radicals, vitamin E can also scavenge reactive nitrogen free radicals. Both of them play important roles in the occurrence and development of NAFLD. In vivo experiments in mice found that vitamin E plays an important regulatory role in improving glucose and lipid metabolism, and vitamin E supplementation can significantly improve lipid metabolism in NAFLD mice. Clinical trials have found that vitamin E supplementation can significantly improve liver pathological outcomes in non-diabetic NAFLD patients [65]. However, there was no significant improvement in diabetic patients with NAFLD [66]. Therefore, vitamin E therapy can be considered for non-diabetic NASH patients who have failed lifestyle interventions.
Peroxisome proliferator-activated receptors (PPARs) are members of the nuclear receptor superfamily of ligand-activated transcription factors. PPARs contain three isoforms consisting of PPARα, PPARβ/δ, and PPARγ. Among them, PPARα is abundantly expressed in hepatocytes. PPARα has a key role in regulating fatty acid transport as well as peroxisomal and mitochondrial β-oxidation in the liver. The researchers found that PPARα expression in the human liver was inversely correlated with the severity of NAFLD. Currently, PPARα-agonists have been shown to improve IR and significantly increase energy expenditure. PPARα-agonists improve pathological conditions in a NAFLD mouse model by modulating lipid turnover and energy metabolism in the liver [67].
9.5.4 Farnesoid X receptor agonists
Farnesoid X Receptor (FXR) is a bile acid receptor, a member of the nuclear receptor superfamily. Studies have found that the nuclear receptor transcription factor FXR can participate in the regulation of various metabolic pathways through the regulation of its corresponding target genes. FXR and retinol X receptor (RXR) bind to the FXR response element in the promoter region of target genes in the form of heterodimers to regulate the transcription of downstream genes. Fibroblast growth factor 21 (FGF21) is an important cytokine downstream of FXR that regulates glucose and lipid metabolism in the body. It can enhance the hydrolysis of adipose tissue, thereby increasing the rate of fatty acid oxidation. Activation of FXR by bile acids can increase the expression and secretion of FGF21, and the increased expression of FGF21 can reduce the content of triglycerides in the liver. Therefore, it can be used as an important drug target for NAFLD [68]. Obeticholic acid is a kind of FXR. In a phase 3 study in the treatment of NAFLD, 25 mg of Obeticholic acid significantly improved fibrosis in NASH patients [69]. Therefore, FXR agonists may also beconsidered as one of the potential drugs for NAFLD.
10. Future prospects
Several issues related to NAFLD require further research to clarify. Furthermore, the lack of understanding of the pathogenesis, causality, and genetic factors of NAFLD have hindered the development of new therapeutics. Therefore, further basic and clinical studies are needed to better understand the development of NAFLD from the perspectives of genetic, molecular, and cell signaling, etc. Focusing on the underlying mechanisms may be valuable in identifying new therapeutic targets for metabolic diseases. Lifestyle interventions are the recommended initial therapy for the treatment of NAFLD. To date, there is insufficient evidence to support the use of drugs that primarily target the underlying causes of MetS. Therefore, if lifestyle changes are not sufficient, other measures that target individual risk factors may be needed. Most importantly, improved strategies are needed to achieve and maintain long-term weight loss and increased physical activity. In future research, not only basic medical research will be conducted but also actively innovate and carry out translational medicines. It is believed that with the joint efforts of medicinal chemists and clinical experts, new drugs will be used in the treatment of liver diseases.
Acknowledgments
This work is supported by research grants from the National Natural Science Foundation of China (31471330), National Key R&D Program of China (2020YFC2006100 and 2020YFC2006101), National Key R&D Program of China (2020YFC2009000 and 2020YFC2009006), Henan Provincial Key R&D and Promotion Special Project (212102310033), Zhengzhou University Discipline Key Special Project (XKZDQY202001). Furthermore, we thank Dr. Ihtisham Bukhari (Gastroenterology, The Fifth Affiliated Hospital, Zhengzhou University, Zhengzhou, Henan, China) for his linguistic assistance.
Conflict of interest
The authors declare no conflict of interest.
\n',keywords:"non-alcoholic fatty liver disease, metabolic dysfunction-associated fatty liver disease, insulin resistance, type 2 diabetes mellitus, metabolic syndrome, gut flora, drug",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/80792.pdf",chapterXML:"https://mts.intechopen.com/source/xml/80792.xml",downloadPdfUrl:"/chapter/pdf-download/80792",previewPdfUrl:"/chapter/pdf-preview/80792",totalDownloads:58,totalViews:0,totalCrossrefCites:0,dateSubmitted:"January 17th 2022",dateReviewed:"February 4th 2022",datePrePublished:"March 10th 2022",datePublished:null,dateFinished:"March 9th 2022",readingETA:"0",abstract:"Non-alcoholic fatty liver disease (NAFLD) is diffuse steatosis of hepatocytes and is the most common type of chronic liver disease. The benign and reversible stage of NAFLD is defined as simple fatty liver, which further progresses to non-alcoholic steatohepatitis (NASH), liver fibrosis, and even liver cancer. It is believed that in the future, NASH would be one of the primary reasons for advanced liver failure and the need for liver transplantation. NAFLD is considered to be closely related to genetics, environment, metabolic diseases, such as obesity and hyperlipidemia. From the macro-level of NAFLD understanding, this chapter systematically analyzes the research progress on the etiology, pathogenesis, diagnosis, treatment, and development trends of NAFLD.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/80792",risUrl:"/chapter/ris/80792",signatures:"Youcai Tang, Xuecui Yin and Yuying Ma",book:{id:"11265",type:"book",title:"Hepatotoxicity",subtitle:null,fullTitle:"Hepatotoxicity",slug:null,publishedDate:null,bookSignature:"Dr. Costin Teodor Streba, Dr. Ion Rogoveanu and Dr. Cristin Constantin Vere",coverURL:"https://cdn.intechopen.com/books/images_new/11265.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-80355-781-6",printIsbn:"978-1-80355-780-9",pdfIsbn:"978-1-80355-782-3",isAvailableForWebshopOrdering:!0,editors:[{id:"55546",title:"Dr.",name:"Costin",middleName:"Teodor",surname:"Streba",slug:"costin-streba",fullName:"Costin Streba"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:null,sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Epidemiology",level:"1"},{id:"sec_3",title:"3. Etiology",level:"1"},{id:"sec_4",title:"4. Risk factors",level:"1"},{id:"sec_4_2",title:"4.1 Obesity",level:"2"},{id:"sec_5_2",title:"4.2 Type 2 diabetes mellitus",level:"2"},{id:"sec_6_2",title:"4.3 Metabolic syndrome",level:"2"},{id:"sec_7_2",title:"4.4 Lifestyle",level:"2"},{id:"sec_8_2",title:"4.5 Genetic factors",level:"2"},{id:"sec_9_2",title:"4.6 Gut flora",level:"2"},{id:"sec_11",title:"5. Pathophysiology and pathogenesis",level:"1"},{id:"sec_11_2",title:"5.1 Theoretical hypothesis of “two-hit” and “multiple hit” in NAFLD",level:"2"},{id:"sec_12_2",title:"5.2 Insulin resistance",level:"2"},{id:"sec_13_2",title:"5.3 Lipotoxicity",level:"2"},{id:"sec_14_2",title:"5.4 Endoplasmic reticulum stress",level:"2"},{id:"sec_15_2",title:"5.5 Inflammation",level:"2"},{id:"sec_16_2",title:"5.6 Leptin and adiponectin",level:"2"},{id:"sec_17_2",title:"5.7 Hepatic stellate cells",level:"2"},{id:"sec_19",title:"6. Clinical manifestations",level:"1"},{id:"sec_20",title:"7. Diagnosis",level:"1"},{id:"sec_21",title:"8. Differential diagnosis",level:"1"},{id:"sec_21_2",title:"8.1 Alcoholic liver disease",level:"2"},{id:"sec_22_2",title:"8.2 Chronic viral hepatitis",level:"2"},{id:"sec_23_2",title:"8.3 Autoimmune liver diseases",level:"2"},{id:"sec_24_2",title:"8.4 Hepatolenticular degeneration",level:"2"},{id:"sec_26",title:"9. Treatment",level:"1"},{id:"sec_26_2",title:"9.1 Lifestyle",level:"2"},{id:"sec_27_2",title:"9.2 Obesity management",level:"2"},{id:"sec_28_2",title:"9.3 Pharmacotherapy for patients with T2DM",level:"2"},{id:"sec_29_2",title:"9.4 Gut flora",level:"2"},{id:"sec_30_2",title:"9.5 Potential drugs",level:"2"},{id:"sec_30_3",title:"9.5.1 Curcumin",level:"3"},{id:"sec_31_3",title:"9.5.2 Vitamin E",level:"3"},{id:"sec_32_3",title:"9.5.3 Peroxisome proliferator-activated receptor alpha (PPAR-α) agonist",level:"3"},{id:"sec_33_3",title:"9.5.4 Farnesoid X receptor agonists",level:"3"},{id:"sec_36",title:"10. Future prospects",level:"1"},{id:"sec_37",title:"Acknowledgments",level:"1"},{id:"sec_40",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Eslam M, Newsome PN, Sarin SK, et al. A new definition for metabolic dysfunction-associated fatty liver disease: An international expert consensus statement. Journal of Hepatology. 2020;73(1):202-209. 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Department of Pediatrics, The Fifth Affiliated Hospital, Zhengzhou University, China
Gastroenterology, The Fifth Affiliated Hospital, Zhengzhou University, China
Henan Key Laboratory of Rehabilitation Medicine, The Fifth Affiliated Hospital, Zhengzhou University, China
Henan Joint International Research Laboratory of Chronic Liver Injury, The Fifth Affiliated Hospital, Zhengzhou University, China
Zhengzhou Key Laboratory of Metabolic-dysfunction-associated Fatty Liver Disease, The Fifth Affiliated Hospital, Zhengzhou University, China
Gastroenterology, The Fifth Affiliated Hospital, Zhengzhou University, China
'}],corrections:null},book:{id:"11265",type:"book",title:"Hepatotoxicity",subtitle:null,fullTitle:"Hepatotoxicity",slug:null,publishedDate:null,bookSignature:"Dr. Costin Teodor Streba, Dr. Ion Rogoveanu and Dr. Cristin Constantin Vere",coverURL:"https://cdn.intechopen.com/books/images_new/11265.jpg",licenceType:"CC BY 3.0",editedByType:null,isbn:"978-1-80355-781-6",printIsbn:"978-1-80355-780-9",pdfIsbn:"978-1-80355-782-3",isAvailableForWebshopOrdering:!0,editors:[{id:"55546",title:"Dr.",name:"Costin",middleName:"Teodor",surname:"Streba",slug:"costin-streba",fullName:"Costin Streba"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}}},profile:{item:{id:"25222",title:"Dr.",name:"Dong",middleName:null,surname:"Jiang",email:"jiangd@igsnrr.ac.cn",fullName:"Dong Jiang",slug:"dong-jiang",position:null,biography:null,institutionString:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",totalCites:0,totalChapterViews:"0",outsideEditionCount:0,totalAuthoredChapters:"4",totalEditedBooks:"0",personalWebsiteURL:null,twitterURL:null,linkedinURL:null,institution:null},booksEdited:[],chaptersAuthored:[{id:"45735",title:"Investigation of Image Fusion for Remote Sensing Application",slug:"investigation-of-image-fusion-for-remote-sensing-application",abstract:null,signatures:"Dong Jiang, Dafang Zhuang and Yaohuan Huang",authors:[{id:"25222",title:"Dr.",name:"Dong",surname:"Jiang",fullName:"Dong Jiang",slug:"dong-jiang",email:"jiangd@igsnrr.ac.cn"}],book:{id:"3081",title:"New Advances in Image Fusion",slug:"new-advances-in-image-fusion",productType:{id:"1",title:"Edited Volume"}}},{id:"49930",title:"Monitoring the Coastal Environment Using Remote Sensing and GIS Techniques",slug:"monitoring-the-coastal-environment-using-remote-sensing-and-gis-techniques",abstract:"The coastal zone has been of importance for economic development and ecological restoration due to their rich natural resources and vulnerable ecosystems. Remote sensing techniques have proven to be powerful tools for the monitoring of the Earth’s surface and atmosphere on a global, regional, and even local scale, by providing important coverage, mapping and classification of land cover features such as vegetation, soil, water and forests. This chapter introduced the methods for monitoring the coastal environment using remote sensing and GIS techniques. Case studies of port expansion monitoring in typical coastal regions, together with the coastal environment changes analysis were also presented.",signatures:"Dong Jiang, Mengmeng Hao and Jingying Fu",authors:[{id:"25222",title:"Dr.",name:"Dong",surname:"Jiang",fullName:"Dong Jiang",slug:"dong-jiang",email:"jiangd@igsnrr.ac.cn"},{id:"176843",title:"Dr.",name:"Jingying",surname:"Fu",fullName:"Jingying Fu",slug:"jingying-fu",email:"fujy@lreis.ac.cn"},{id:"176844",title:"MSc.",name:"Mengmeng",surname:"Hao",fullName:"Mengmeng Hao",slug:"mengmeng-hao",email:"haomm.12s@igsnrr.ac.cn"}],book:{id:"5096",title:"Applied Studies of Coastal and Marine Environments",slug:"applied-studies-of-coastal-and-marine-environments",productType:{id:"1",title:"Edited Volume"}}},{id:"50401",title:"Sustainable Urbanization in the China‐Indochinese Peninsula Economic Corridor",slug:"sustainable-urbanization-in-the-china-indochinese-peninsula-economic-corridor",abstract:"Countries in the China‐Indochinese Peninsula are home to rich human and natural resource endowments and have the potential to be one of the world's fastest growing areas. Sustainable urbanization in the China‐Indochinese Peninsula Economic Corridor is important for the regional economic development and prosperity. Taking the advantages of the remote sensing and Geographic Information System (GIS) technologies, this chapter is first presents a general overview of urbanization procession in this region and monitors the spatiotemporal dynamics of the urban environment; the second objective is to present the multiple driving force factor analysis for urban development in countries of the China‐Indochinese Peninsula Economic Corridor using statistical models. The results indicated that the China‐Indochinese Peninsula Economic Corridor has experienced a rapid urbanization process during the past 15 years both in terms of urban areas and urban population (UP). In addition to socioeconomic factors, there is also a noticeable correlation between foreign direct investment (FDI) and international trade and urban development in the China‐Indochinese Peninsula Economic Corridor. Active participation in international trade and attracting foreign investment are helpful for the regional urbanization. As a neighboring country, China's economic and trade activity also has a significant impact on the urbanization in countries of the China‐Indochinese Peninsula Economic Corridor. Furthermore, as the launch of the Silk Road Economic Belt and the 21st Century Maritime Silk Road and the Asian Infrastructure Investment Bank (AIIB), the China‐Indochinese Peninsula Economic Corridor will witness a more rapid urbanization progress in the next decade. This study has its characteristics in focusing on the region of the Indochinese Peninsula in which the most rapid urbanization is occurring, presenting the state‐of‐the‐art techniques for monitoring urban expansion and probing into the driving factors of the urban expansion in the China‐Indochinese Peninsula Economic Corridor by multiple principles and multiple‐level data. It is expected to benefit policymakers in urban development and also provide a basis for further studies of sustainable urbanization in the China‐Indochinese Peninsula Economic Corridor.",signatures:"Dong Jiang, Jingying Fu and Gang Lin",authors:[{id:"25222",title:"Dr.",name:"Dong",surname:"Jiang",fullName:"Dong Jiang",slug:"dong-jiang",email:"jiangd@igsnrr.ac.cn"},{id:"180532",title:"Dr.",name:"Jingying",surname:"Fu",fullName:"Jingying Fu",slug:"jingying-fu",email:"fujy@igsnrr.ac.cn"},{id:"181037",title:"Dr.",name:"Gang",surname:"Lin",fullName:"Gang Lin",slug:"gang-lin",email:"ling@lreis.ac.cn"}],book:{id:"5235",title:"Sustainable Urbanization",slug:"sustainable-urbanization",productType:{id:"1",title:"Edited Volume"}}},{id:"52074",title:"Energy-Water Balance and Ecosystem Response to Climate Change in Southwest China",slug:"energy-water-balance-and-ecosystem-response-to-climate-change-in-southwest-china",abstract:"It is important to highlight energy-water balance and ecosystem response to climate changes. The change of water-energy balance and ecosystem due to climate change will affect the regional ecological and human living significantly, especially in Southwest China which is an ecologically fragile area. This chapter presents the retrieval methodology of parameters (reconstruction of vegetation index, land cover semi-automatic classification, a time series reconstruction of land surface temperature based on Kalman filter and precipitation interpolation based on thin plate smoothing splines), time-series analysis methodology (land cover change, vegetation succession and drought index) and correlate analysis methodology (correlation coefficient and principal component analysis). Then, based on the above method, remote sensing data were integrated, a time series analysis on a 30-year data was used to illustrate the water-energy balance and ecosystem variability in Southwest China. The result showed that energy-water balance and ecosystem (ecosystem structures, vegetation and droughts) have severe response to climate change.",signatures:"Jianhua Wang, Yaohuan Hang, Dong Jiang and Xiaoyang Song",authors:[{id:"25222",title:"Dr.",name:"Dong",surname:"Jiang",fullName:"Dong Jiang",slug:"dong-jiang",email:"jiangd@igsnrr.ac.cn"},{id:"181018",title:"Prof.",name:"Jianhua",surname:"Wang",fullName:"Jianhua Wang",slug:"jianhua-wang",email:"wjh@iwhr.com"},{id:"181019",title:"Dr.",name:"Yaohuan",surname:"Huang",fullName:"Yaohuan Huang",slug:"yaohuan-huang",email:"huangyh@igsnrr.ac.cn"},{id:"185478",title:"Ms.",name:"Xiaoyang",surname:"Song",fullName:"Xiaoyang Song",slug:"xiaoyang-song",email:"songxiaoyang.good@163.com"}],book:{id:"5221",title:"Topics in Climate Modeling",slug:"topics-in-climate-modeling",productType:{id:"1",title:"Edited Volume"}}}],collaborators:[{id:"18665",title:"Prof.",name:"Farah",surname:"Imed Riadh",slug:"farah-imed-riadh",fullName:"Farah Imed Riadh",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:"Perso.telecom-bretagne.eu/imedfarah/",institutionString:null,institution:{name:"Manouba University",institutionURL:null,country:{name:"Tunisia"}}},{id:"19360",title:"Ms.",name:"Poonam",surname:"S. Tiwari",slug:"poonam-s.-tiwari",fullName:"Poonam S. Tiwari",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"20813",title:"Dr.",name:"Hemissi",surname:"Selim",slug:"hemissi-selim",fullName:"Hemissi Selim",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"20905",title:"Dr.",name:"Ibrahim",surname:"Elshafiey",slug:"ibrahim-elshafiey",fullName:"Ibrahim Elshafiey",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"King Saud University",institutionURL:null,country:{name:"Saudi Arabia"}}},{id:"20907",title:"Prof.",name:"Majeed",surname:"Alkanhal",slug:"majeed-alkanhal",fullName:"Majeed Alkanhal",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"22554",title:"Ms",name:"Hina",surname:"Pande",slug:"hina-pande",fullName:"Hina Pande",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"24502",title:"Dr.",name:"Yufeng",surname:"Zheng",slug:"yufeng-zheng",fullName:"Yufeng Zheng",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/24502/images/3995_n.jpg",biography:"Yufeng Zheng received his Ph.D. degree in Optical Engineering/Image Processing from Tianjin University (Tianjin, China) in 1997. He is presently with Alcorn State University (Mississippi, USA) as an associate professor. Dr. Zheng serves as a program director of the Computer Network and Information Technology major, as well as the director of Pattern Recognition and Image Analysis Lab. He is the principle investigator on three federal research grants in night vision enhancement, thermal face recognition, and multispectral face recognition. He was the Co-PI on a breast cancer detection research grant. Dr. Zheng holds two patents on glaucoma classification and face recognition, and has published one book, six book chapters, and more than 70 peer-reviewed papers. His research interests include biomedical imaging, pattern recognition, biometrics, information fusion, colorization, bio-inspired image analysis, and computer-aided diagnosis. Dr. Zheng is a Cisco Certified Network Professional (CCNP), a senior member of SPIE, a member of IEEE & Computer Society, as well as a technical reviewer.",institutionString:null,institution:null},{id:"151689",title:"Mr.",name:"Dr. Md Anowar",surname:"Hossain",slug:"dr.-md-anowar-hossain",fullName:"Dr. Md Anowar Hossain",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/151689/images/2259_n.jpg",biography:"Md Anowar Hossain received his B.Sc. degree in Computer and Communication Engineering from International Islamic University Chittagong (IIUC), Bangladesh in 2005. He received M.Sc. and PhD degree in Electrical Engineering from King Saud University, Saudi Arabia in 2013 and 2018 respectively. Currently, he is working as DSP Engineer in Prince Sultan Defense Studies and Research Center (PSDSARC). His research interests include UWB radar; synthetic aperture radar (SAR) imaging; radar jamming and anti-jamming; radar signal processing and FPGA based real-time signal processing , vehicular communication and Intelligent transportation system.",institutionString:null,institution:{name:"King Saud University",institutionURL:null,country:{name:"Saudi Arabia"}}},{id:"152647",title:"Dr",name:null,surname:"Chen",slug:"chen",fullName:"Chen",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"155583",title:"Dr.",name:"Qiguang",surname:"Miao",slug:"qiguang-miao",fullName:"Qiguang Miao",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/155583/images/system/155583.jpg",biography:"Qiguang Miao is a professor and Ph.D. supervisor of School of Computer Science and Technology in Xidian University. In 2012, he was supported by the Program for New Century Excellent Talents in University by Ministry of Education. He received his doctor degree in computer application technology from Xidian University in December 2005. In the field of teaching, he was awarded as one of Pacemaker of Ten Excellent Teacher twice in 2008 and 2011. His research interests include machine learning, intelligent image processing and malware behavior analysis and understanding. As principal investigator, he is doing or has completed 3 projects of NSFC, 2 projects of Shaanxi provincial natural science fund, more than 10 projects of National Defence Pre-research Foundation, 863 and Weapons and Equipment fund. He has published over 50 papers in the significant domestic and international journal or conference.",institutionString:null,institution:{name:"Xidian University",institutionURL:null,country:{name:"China"}}}]},generic:{page:{slug:"OA-publishing-fees",title:"Open Access Publishing Fees",intro:"
The Open Access model is applied to all of our publications and is designed to eliminate subscriptions and pay-per-view fees. This approach ensures free, immediate access to full text versions of your research.
As a gold Open Access publisher, an Open Access Publishing Fee is payable on acceptance following peer review of the manuscript. In return, we provide high quality publishing services and exclusive benefits for all contributors. IntechOpen is the trusted publishing partner of over 140,000 international scientists and researchers.
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1,400 GBP Chapter - Edited Volume
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4,000 GBP Compacts Monograph - Short Form
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850 GBP Journal Article (Across Portfolio)
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*These prices do not include Value-Added Tax (VAT). Residents of European Union countries need to add VAT based on the specific rate in their country of residence. Institutions and companies registered as VAT taxable entities in their own EU member state will not pay VAT as long as provision of the VAT registration number is made during the application process. This is made possible by the EU reverse charge method.
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Services included are:
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XML Typesetting and pagination - web (PDF, HTML) and print files preparation
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Discoverability - electronic citation and linking via DOI
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Permanent and unrestricted online access to your work
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What isn't covered by the Open Access Publishing Fee?
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Exceeds the number of pages defined by the publishing guidelines, an additional fee per page may be required
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Your Author Service Manager will inform you of any items not covered by the OAPF and provide exact information regarding those additional costs before proceeding.
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Open Access Funding
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To explore funding opportunities and learn more about how you can finance your IntechOpen publication, go to our Open Access Funding page. IntechOpen offers expert assistance to all of its Authors. We can support you in approaching funding bodies and institutions in relation to publishing fees by providing information about compliance with the Open Access policies of your funder or institution. We can also assist with communicating the benefits of Open Access in order to support and strengthen your funding request and provide personal guidance through your application process. You can contact us at funders@intechopen.com for further details or assistance.
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For Authors who are still unable to obtain funding from their institutions or research funding bodies for individual projects, IntechOpen does offer the possibility of applying for a Waiver to offset some or all processing feed. Details regarding our Waiver Policy can be found here.
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Added Value of Publishing with IntechOpen
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Choosing to publish with IntechOpen ensures the following benefits:
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Indexing and listing across major repositories, see details ...
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Long-term archiving
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Visibility on the world's strongest OA platform
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Live Performance Metrics to track readership and the impact of your chapter
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Dissemination and Promotion
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Benefits of Publishing with IntechOpen
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Proven world leader in Open Access book publishing with over 10 years experience
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+5,700 OA books published
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Most competitive prices in the market
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Fully compliant with OA funding requirements
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Optimized processes that assure your research is made available to the scientific community without delay
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Personal support during every step of the publication process
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+184,650 citations in Web of Science databases
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Currently strongest OA platform with over 175 million downloads
As a gold Open Access publisher, an Open Access Publishing Fee is payable on acceptance following peer review of the manuscript. In return, we provide high quality publishing services and exclusive benefits for all contributors. IntechOpen is the trusted publishing partner of over 140,000 international scientists and researchers.
\n\n
The Open Access Publishing Fee (OAPF) is payable only after your book chapter, monograph or journal article is accepted for publication.
\n\n
OAPF Publishing Options
\n\n
\n\t
1,400 GBP Chapter - Edited Volume
\n\t
850 GBP Chapter - Book Series Topic (Annual Volume)
\n\t
10,000 GBP Monograph - Long Form
\n\t
4,000 GBP Compacts Monograph - Short Form
\n\t
850 GBP Journal Article (Across Portfolio)
\n
\n\n
During the launching phase journals do not charge an APC, rather they will be funded by IntechOpen.
\n\n
*These prices do not include Value-Added Tax (VAT). Residents of European Union countries need to add VAT based on the specific rate in their country of residence. Institutions and companies registered as VAT taxable entities in their own EU member state will not pay VAT as long as provision of the VAT registration number is made during the application process. This is made possible by the EU reverse charge method.
\n\n
Services included are:
\n\n
\n\t
An online manuscript tracking system to facilitate your work
\n\t
Personal contact and support throughout the publishing process from your dedicated Author Service Manager
\n\t
Assurance that your manuscript meets the highest publishing standards
\n\t
English language copyediting and proofreading, including the correction of grammatical, spelling, and other common errors
\n\t
XML Typesetting and pagination - web (PDF, HTML) and print files preparation
\n\t
Discoverability - electronic citation and linking via DOI
\n\t
Permanent and unrestricted online access to your work
\n
\n\n
What isn't covered by the Open Access Publishing Fee?
\n\n
If your manuscript:
\n\n
\n\t
Exceeds the number of pages defined by the publishing guidelines, an additional fee per page may be required
\n\t
If a manuscript requires Heavy Editing or Language Polishing, this will incur additional fees.
\n
\n\n
Your Author Service Manager will inform you of any items not covered by the OAPF and provide exact information regarding those additional costs before proceeding.
\n\n
Open Access Funding
\n\n
To explore funding opportunities and learn more about how you can finance your IntechOpen publication, go to our Open Access Funding page. IntechOpen offers expert assistance to all of its Authors. We can support you in approaching funding bodies and institutions in relation to publishing fees by providing information about compliance with the Open Access policies of your funder or institution. We can also assist with communicating the benefits of Open Access in order to support and strengthen your funding request and provide personal guidance through your application process. You can contact us at funders@intechopen.com for further details or assistance.
\n\n
For Authors who are still unable to obtain funding from their institutions or research funding bodies for individual projects, IntechOpen does offer the possibility of applying for a Waiver to offset some or all processing feed. Details regarding our Waiver Policy can be found here.
\n\n
Added Value of Publishing with IntechOpen
\n\n
Choosing to publish with IntechOpen ensures the following benefits:
\n\n
\n\t
Indexing and listing across major repositories, see details ...
\n\t
Long-term archiving
\n\t
Visibility on the world's strongest OA platform
\n\t
Live Performance Metrics to track readership and the impact of your chapter
\n\t
Dissemination and Promotion
\n
\n\n
Benefits of Publishing with IntechOpen
\n\n
\n\t
Proven world leader in Open Access book publishing with over 10 years experience
\n\t
+5,700 OA books published
\n\t
Most competitive prices in the market
\n\t
Fully compliant with OA funding requirements
\n\t
Optimized processes that assure your research is made available to the scientific community without delay
\n\t
Personal support during every step of the publication process
\n\t
+184,650 citations in Web of Science databases
\n\t
Currently strongest OA platform with over 175 million downloads
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\n'}]},successStories:{items:[]},authorsAndEditors:{filterParams:{},profiles:[{id:"396",title:"Dr.",name:"Vedran",middleName:null,surname:"Kordic",slug:"vedran-kordic",fullName:"Vedran Kordic",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/396/images/7281_n.png",biography:"After obtaining his Master's degree in Mechanical Engineering he continued his education at the Vienna University of Technology where he obtained his PhD degree in 2004. He worked as a researcher at the Automation and Control Institute, Faculty of Electrical Engineering, Vienna University of Technology until 2008. His studies in robotics lead him not only to a PhD degree but also inspired him to co-found and build the International Journal of Advanced Robotic Systems - world's first Open Access journal in the field of robotics.",institutionString:null,institution:{name:"TU Wien",country:{name:"Austria"}}},{id:"441",title:"Ph.D.",name:"Jaekyu",middleName:null,surname:"Park",slug:"jaekyu-park",fullName:"Jaekyu Park",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/441/images/1881_n.jpg",biography:null,institutionString:null,institution:{name:"LG Corporation (South Korea)",country:{name:"Korea, South"}}},{id:"465",title:"Dr",name:"Christian",middleName:null,surname:"Martens",slug:"christian-martens",fullName:"Christian Martens",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:null},{id:"479",title:"Dr.",name:"Valentina",middleName:null,surname:"Colla",slug:"valentina-colla",fullName:"Valentina Colla",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/479/images/358_n.jpg",biography:null,institutionString:null,institution:{name:"Sant'Anna School of Advanced Studies",country:{name:"Italy"}}},{id:"494",title:"PhD",name:"Loris",middleName:null,surname:"Nanni",slug:"loris-nanni",fullName:"Loris Nanni",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/494/images/system/494.jpg",biography:"Loris Nanni received his Master Degree cum laude on June-2002 from the University of Bologna, and the April 26th 2006 he received his Ph.D. in Computer Engineering at DEIS, University of Bologna. On September, 29th 2006 he has won a post PhD fellowship from the university of Bologna (from October 2006 to October 2008), at the competitive examination he was ranked first in the industrial engineering area. He extensively served as referee for several international journals. He is author/coauthor of more than 100 research papers. He has been involved in some projects supported by MURST and European Community. His research interests include pattern recognition, bioinformatics, and biometric systems (fingerprint classification and recognition, signature verification, face recognition).",institutionString:null,institution:null},{id:"496",title:"Dr.",name:"Carlos",middleName:null,surname:"Leon",slug:"carlos-leon",fullName:"Carlos Leon",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Seville",country:{name:"Spain"}}},{id:"512",title:"Dr.",name:"Dayang",middleName:null,surname:"Jawawi",slug:"dayang-jawawi",fullName:"Dayang Jawawi",position:null,profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",biography:null,institutionString:null,institution:{name:"University of Technology Malaysia",country:{name:"Malaysia"}}},{id:"528",title:"Dr.",name:"Kresimir",middleName:null,surname:"Delac",slug:"kresimir-delac",fullName:"Kresimir Delac",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/528/images/system/528.jpg",biography:"K. Delac received his B.Sc.E.E. degree in 2003 and is currentlypursuing a Ph.D. degree at the University of Zagreb, Faculty of Electrical Engineering andComputing. His current research interests are digital image analysis, pattern recognition andbiometrics.",institutionString:null,institution:{name:"University of Zagreb",country:{name:"Croatia"}}},{id:"557",title:"Dr.",name:"Andon",middleName:"Venelinov",surname:"Topalov",slug:"andon-topalov",fullName:"Andon Topalov",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/557/images/1927_n.jpg",biography:"Dr. Andon V. Topalov received the MSc degree in Control Engineering from the Faculty of Information Systems, Technologies, and Automation at Moscow State University of Civil Engineering (MGGU) in 1979. He then received his PhD degree in Control Engineering from the Department of Automation and Remote Control at Moscow State Mining University (MGSU), Moscow, in 1984. From 1985 to 1986, he was a Research Fellow in the Research Institute for Electronic Equipment, ZZU AD, Plovdiv, Bulgaria. In 1986, he joined the Department of Control Systems, Technical University of Sofia at the Plovdiv campus, where he is presently a Full Professor. He has held long-term visiting Professor/Scholar positions at various institutions in South Korea, Turkey, Mexico, Greece, Belgium, UK, and Germany. And he has coauthored one book and authored or coauthored more than 80 research papers in conference proceedings and journals. His current research interests are in the fields of intelligent control and robotics.",institutionString:null,institution:{name:"Technical University of Sofia",country:{name:"Bulgaria"}}},{id:"585",title:"Prof.",name:"Munir",middleName:null,surname:"Merdan",slug:"munir-merdan",fullName:"Munir Merdan",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/585/images/system/585.jpg",biography:"Munir Merdan received the M.Sc. degree in mechanical engineering from the Technical University of Sarajevo, Bosnia and Herzegovina, in 2001, and the Ph.D. degree in electrical engineering from the Vienna University of Technology, Vienna, Austria, in 2009.Since 2005, he has been at the Automation and Control Institute, Vienna University of Technology, where he is currently a Senior Researcher. His research interests include the application of agent technology for achieving agile control in the manufacturing environment.",institutionString:null,institution:null},{id:"605",title:"Prof",name:"Dil",middleName:null,surname:"Hussain",slug:"dil-hussain",fullName:"Dil Hussain",position:null,profilePictureURL:"https://mts.intechopen.com/storage/users/605/images/system/605.jpg",biography:"Dr. Dil Muhammad Akbar Hussain is a professor of Electronics Engineering & Computer Science at the Department of Energy Technology, Aalborg University Denmark. Professor Akbar has a Master degree in Digital Electronics from Govt. College University, Lahore Pakistan and a P-hD degree in Control Engineering from the School of Engineering and Applied Sciences, University of Sussex United Kingdom. Aalborg University has Two Satellite Campuses, one in Copenhagen (Aalborg University Copenhagen) and the other in Esbjerg (Aalborg University Esbjerg).\n· He is a member of prestigious IEEE (Institute of Electrical and Electronics Engineers), and IAENG (International Association of Engineers) organizations. \n· He is the chief Editor of the Journal of Software Engineering.\n· He is the member of the Editorial Board of International Journal of Computer Science and Software Technology (IJCSST) and International Journal of Computer Engineering and Information Technology. \n· He is also the Editor of Communication in Computer and Information Science CCIS-20 by Springer.\n· Reviewer For Many Conferences\nHe is the lead person in making collaboration agreements between Aalborg University and many universities of Pakistan, for which the MOU’s (Memorandum of Understanding) have been signed.\nProfessor Akbar is working in Academia since 1990, he started his career as a Lab demonstrator/TA at the University of Sussex. After finishing his P. hD degree in 1992, he served in the Industry as a Scientific Officer and continued his academic career as a visiting scholar for a number of educational institutions. In 1996 he joined National University of Science & Technology Pakistan (NUST) as an Associate Professor; NUST is one of the top few universities in Pakistan. In 1999 he joined an International Company Lineo Inc, Canada as Manager Compiler Group, where he headed the group for developing Compiler Tool Chain and Porting of Operating Systems for the BLACKfin processor. The processor development was a joint venture by Intel and Analog Devices. In 2002 Lineo Inc., was taken over by another company, so he joined Aalborg University Denmark as an Assistant Professor.\nProfessor Akbar has truly a multi-disciplined career and he continued his legacy and making progress in many areas of his interests both in teaching and research. 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The problematic is presented, and motor impairments for upper and lower limbs are characterized. 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Researchers and students will find the chapter appealing with a preliminary description of P300 ERP. This chapter also appreciates the importance and advantages of noninvasive ERP technique. In noninvasive BCI, the P300 ERPs are extracted from brain electrical activities [electroencephalogram (EEG)] as a signature of the underlying electrophysiological mechanism of brain responses to the external or internal changes and events. As the chapter proceeds, topics are covered on more relevant scholarly works about challenges and new directions in P300 BCI. Along with these, articles with the references on the advancement of this technique will be presented to ensure that the scholarly reviews are accessible to people who are new to this field. To enhance fundamental understanding, stimulation as well as signal processing methods will be discussed from some novel works with a comparison of the associated results. 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It is enshrined in posterior cranial fossa behind the pons and medulla oblongata and separated from these structures by cavity of fourth ventricle. It is connected to brainstem by three fibre tracts known as cerebellar peduncles. Cerebellum controls the same side of body. It precisely coordinates skilled voluntary movements by controlling strength, duration and force of contraction, so that they are smooth, balanced and accurate. It is also responsible for maintaining equilibrium, muscle tone and posture of the body. This is achieved through the use of somatic sensory information in modulating the motor output from the cerebrum and brainstem. Sherrington regarded cerebellum as the head ganglion of the proprioceptive system. Dysfunction of cerebellum along with degenerative diseases of cerebellum such as spinocerebellar ataxia, multiple sclerosis, malignant tumours, etc. may culminate into disequilibrium, hypotonia, difficulty in talking, sleeping, maintaining muscular coordination and dyssynergia which at times may be life threatening. Hence, knowledge of anatomy of cerebellum is imperative for neuroanatomists and neurosurgeons.",book:{id:"9157",slug:"neurodegenerative-diseases-molecular-mechanisms-and-current-therapeutic-approaches",title:"Neurodegenerative Diseases",fullTitle:"Neurodegenerative Diseases - Molecular Mechanisms and Current Therapeutic Approaches"},signatures:"Rajani Singh",authors:[{id:"319468",title:"Dr.",name:"Rajani",middleName:null,surname:"Singh",slug:"rajani-singh",fullName:"Rajani Singh"}]},{id:"55773",title:"Event-Related Potentials for the Study of Cognition",slug:"event-related-potentials-for-the-study-of-cognition",totalDownloads:1528,totalCrossrefCites:2,totalDimensionsCites:3,abstract:"Despite the vast literature on event-related potentials (ERPs), many clinical professionals are still unaware of the huge variety of possible applications they offer. The aim of this chapter is not to show the classical use of ERPs, focused on analyzing the first steps of information processing (sensory pathways). On the contrary, this chapter will be focused on the use of these ERPs in the assessment of cognitive function. In particular, this chapter is mainly focused on the use of ERPs to better understand the neural bases of cognitive impairment from the electrical activity of the brain. Describing all the possible ERP components and their cognitive meaning is a huge endeavor, and this chapter will only be focused on three of them: contingent negative variation (CNV), mismatch negativity (MMN), and P300. To improve the reader’s knowledge about these ERPs in cognition, a specific description will be given about the stimulation required to obtain the specific component, the topography, and latency shown. Moreover, a description of the neurophysiological bases of the component, its relationship with psychological processes and neural sources will be also included. Pathological alterations suffered by the component will also be briefly described.",book:{id:"5751",slug:"event-related-potentials-and-evoked-potentials",title:"Event-Related Potentials and Evoked Potentials",fullTitle:"Event-Related Potentials and Evoked Potentials"},signatures:"Manuel Vazquez-Marrufo",authors:[{id:"189375",title:"Dr.",name:"Manuel",middleName:null,surname:"Vazquez-Marrufo",slug:"manuel-vazquez-marrufo",fullName:"Manuel Vazquez-Marrufo"}]},{id:"46092",title:"A Practical Guide to an fMRI Experiment",slug:"a-practical-guide-to-an-fmri-experiment",totalDownloads:3147,totalCrossrefCites:0,totalDimensionsCites:1,abstract:null,book:{id:"4461",slug:"advanced-brain-neuroimaging-topics-in-health-and-disease-methods-and-applications",title:"Advanced Brain Neuroimaging Topics in Health and Disease",fullTitle:"Advanced Brain Neuroimaging Topics in Health and Disease - Methods and Applications"},signatures:"Nasser Kashou",authors:[{id:"77988",title:"Dr.",name:"Nasser",middleName:"H",surname:"Kashou",slug:"nasser-kashou",fullName:"Nasser Kashou"}]}],onlineFirstChaptersFilter:{topicId:"1059",limit:6,offset:0},onlineFirstChaptersCollection:[{id:"81566",title:"New and Emerging Technologies for Integrative Ambulatory Autonomic Assessment and Intervention as a Catalyst in the Synergy of Remote Geocoded Biosensing, Algorithmic Networked Cloud Computing, Deep Learning, and Regenerative/Biomic Medicine: Further Real",slug:"new-and-emerging-technologies-for-integrative-ambulatory-autonomic-assessment-and-intervention-as-a-",totalDownloads:17,totalDimensionsCites:0,doi:"10.5772/intechopen.104092",abstract:"While the important role of the autonomic nervous system (ANS) has been historically underappreciated, recently there has been a rapid proliferation of empirical, methodological and theoretical progress in our more detailed understanding of the ANS. Previous more simplistic models of the role of the ANS using the construct of homeostasis have been enhanced by the use of the construct of allostasis and a wide variety of technological innovations including wearable and implantable biosensors have led to improved understanding of both basic and applied knowledge. This chapter will explore in particular heart rate variability (HRV) as a rich variable which has developed an extensive literature, beginning with predicting all-cause mortality, but now encompassing a wide variety of disease and illness states; cognitive, affective and behavioral processes and performance optimization. A critical analysis of HRV from the perspective of complex adaptive systems and non-linear processes will be included and innovative future uses of HRV will be described.",book:{id:"10835",title:"Autonomic Nervous System - Special Interest Topics",coverURL:"https://cdn.intechopen.com/books/images_new/10835.jpg"},signatures:"Robert L. Drury"},{id:"80895",title:"Heart Rate Variability as a Marker of Homeostatic Level",slug:"heart-rate-variability-as-a-marker-of-homeostatic-level",totalDownloads:35,totalDimensionsCites:0,doi:"10.5772/intechopen.102500",abstract:"Many variables have been used as homeostatic level markers. Heart Rate Variability (HRV) has been frequently cited as an indicator of homeostatic status. Low levels of HRV are associated with aging, disease, or increased risk of death. We present a study based on more than 10.5 million data collected from the literature, associating the degree of global clinical impairment of individuals, with their respective HRV data, seeking to establish a classification of Homeostatic Levels. Three specific variables were evaluated: heart rate (HR), the root-mean-square of successive differences between adjacent normal RR intervals in a time interval (RMSSD) and the HF band (HF ms2). It was possible to detect significant differences between the 83,927 data from healthy individuals and the 382,039 data from individuals with significant homeostatic impairment. It was demonstrated that the RMSSD is very sensitive to the worst homeostatic state, presenting a behavior independent of age and that the values found in the general population do not match the values of apparently healthy individuals. An alphanumeric classification of the homeostatic level in a three-level architecture was proposed, with three stages for each level, which may be extremely useful in prognostic assessment and decision-making about individual people.",book:{id:"10835",title:"Autonomic Nervous System - Special Interest Topics",coverURL:"https://cdn.intechopen.com/books/images_new/10835.jpg"},signatures:"Moacir Fernandes de Godoy and Michele Lima Gregório"},{id:"80433",title:"Heart Autonomic Nervous System: Basic Science and Clinical Implications",slug:"heart-autonomic-nervous-system-basic-science-and-clinical-implications",totalDownloads:65,totalDimensionsCites:0,doi:"10.5772/intechopen.101718",abstract:"The heart has an intrinsic conduction system that consists of specialized cells. The heart receives extensive innervation by both sympathetic and parasympathetic systems of the ANS. The ANS influences most heart functions by affecting the SA node, AV node, myocardium, and small and large vessel walls. The sympathetic system carries an excitatory effect on heart functions. Conversely, the parasympathetic system has inhibitory effects on heart functions. ANS abnormalities in terms of anatomy and physiology can cause various heart abnormalities. ANS abnormalities associated with electrical abnormalities can cause a variety of heart manifestations. Besides electrical abnormalities, ANS also correlates with ischemic heart disease. Following electrical and ischemic instability, ANS also have direct effect on action potential duration restitution. By understanding the mechanism of influence of the anatomy and physiology of the ANS heart and its influence on various heart abnormalities, we can determine the appropriate therapeutic approaches. Therapeutic approaches in neurocardiology fall into two focuses: applying novel treatment and interaction of non-drug and multiple drugs treatments.",book:{id:"10835",title:"Autonomic Nervous System - Special Interest Topics",coverURL:"https://cdn.intechopen.com/books/images_new/10835.jpg"},signatures:"Elvan Wiyarta and Nayla Karima"},{id:"80316",title:"Central Control of the Larynx in Mammals",slug:"central-control-of-the-larynx-in-mammals",totalDownloads:45,totalDimensionsCites:0,doi:"10.5772/intechopen.102009",abstract:"Speech is a complex process that requires the coordination of multiple structures of the phonatory system regulated by the central nervous system. Specifically, the larynx is the key point necessary for the vocal folds to come into contact to convert the air that comes out of our lungs into sound. Vocal emission involves the genesis of a precise and prolonged expiration that provides an adequate pressure/air flow component to generate a subglottic pressure compatible with vocalization. The starting point for voluntary vocal production is the laryngeal motor cortex (LMC), a common structure in mammals, although the specific location within the cortex differs in humans. LCM projects to the periaqueductal gray matter (PGM), which leads to pontomedullary structures to locate the generators of laryngeal-respiratory motor patterns, necessary for vocal emission. All these regions present a high expression of FOXP2 transcription factor, necessary for brain and lung development that is closely related to vocalization. These central structures have in common that not only convey cardiorespiratory responses to environmental stress but also support vocalization. At clinical level, recent studies show that central circuits responsible for vocalization present an overactivity in certain speech disorders such as spasmodic dysphonia due to laryngeal dystonia.",book:{id:"10835",title:"Autonomic Nervous System - Special Interest Topics",coverURL:"https://cdn.intechopen.com/books/images_new/10835.jpg"},signatures:"Manuel Víctor López-González, Marta González-García, Laura Carrillo-Franco, Amelia Díaz-Casares and Marc Stefan Dawid-Milner"},{id:"80402",title:"General Anesthesia and Autonomic Nervous System: Control and Management in Neurosurgery",slug:"general-anesthesia-and-autonomic-nervous-system-control-and-management-in-neurosurgery",totalDownloads:70,totalDimensionsCites:0,doi:"10.5772/intechopen.101829",abstract:"The chapter is devoted to the control and management of the autonomic nervous system during general anesthesia in neurosurgery. The brainstem and supratentorial cerebral centers of autonomic regulation are the most important structures for control and management during general anesthesia using pharmacological defense with α2-adrenergic agonists and opioid analgesics. We discuss the questions of the depth of anesthesia (BIS-monitoring) and antinociceptive defense, variability of heart rate (variational cardiointervalometry), hemodynamic monitoring during neurosurgical operation, intraoperative thermometry, the meaning of trigeminocardiac reflex and its classification in neurosurgery, perioperative events causing autonomic distress syndrome development and methods of its prophylaxis and treatment, pathomorphological signs of vegetative distress syndrome. Control of the neuromuscular block and photoplethysmography assessment of perfusion index (PI) as methods of the adequacy of general anesthesia and neurovegetative stability.",book:{id:"10835",title:"Autonomic Nervous System - Special Interest Topics",coverURL:"https://cdn.intechopen.com/books/images_new/10835.jpg"},signatures:"Irina Alexandrovna Savvina, Anna Olegovna Petrova and Yulia Mikhailovna Zabrodskaya"},{id:"80035",title:"Healthy Lifestyle, Autonomic Nervous System Activity, and Sleep Status for Healthy Aging",slug:"healthy-lifestyle-autonomic-nervous-system-activity-and-sleep-status-for-healthy-aging",totalDownloads:72,totalDimensionsCites:0,doi:"10.5772/intechopen.101837",abstract:"With the super-aging society, it is important to pay attention to the quality of life of older people so that they can face healthy aging. Lifestyle, particularly exercise, autonomic nervous system activities, and sleep status are factors that affect the quality of aging. This chapter explores how those three variables are related and what strategies can be employed to maintain and enhance these variables to prepare. (1) The combination of healthy lifestyles, adequate physical activity, healthy dietary patterns, moderate alcohol consumption, and nonsmoking were related to the risk of cardiovascular diseases. (2) For older people, being physically active is important to the improvement of their physical and mental functions and keeping them independent and mobile. The increasing HRV after exercise might be caused by increasing vagal tone and decreasing sympathetic activity. (3) To reach healthy aging, people should maintain the proper function of autonomic balance activities. This is important because slowing down the decline in sympathetic status might delay many geriatric complaints. (4) To achieve healthy aging, maintaining a healthy sleep is essential. Thus, the key to a lifestyle that facilitates healthy aging is a balance of regular physical exercise and adequate sleep, which mediates and is mediated by autonomic nervous system activity.",book:{id:"10835",title:"Autonomic Nervous System - Special Interest Topics",coverURL:"https://cdn.intechopen.com/books/images_new/10835.jpg"},signatures:"Miki Sato, Feni Betriana, Ryuichi Tanioka, Kyoko Osaka, Tetsuya Tanioka and Savina Schoenhofer"}],onlineFirstChaptersTotal:9},preDownload:{success:null,errors:{}},subscriptionForm:{success:null,errors:{}},aboutIntechopen:{},privacyPolicy:{},peerReviewing:{},howOpenAccessPublishingWithIntechopenWorks:{},sponsorshipBooks:{sponsorshipBooks:[],offset:8,limit:8,total:0},allSeries:{pteSeriesList:[{id:"14",title:"Artificial Intelligence",numberOfPublishedBooks:9,numberOfPublishedChapters:89,numberOfOpenTopics:6,numberOfUpcomingTopics:0,issn:"2633-1403",doi:"10.5772/intechopen.79920",isOpenForSubmission:!0},{id:"7",title:"Biomedical Engineering",numberOfPublishedBooks:12,numberOfPublishedChapters:104,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2631-5343",doi:"10.5772/intechopen.71985",isOpenForSubmission:!0}],lsSeriesList:[{id:"11",title:"Biochemistry",numberOfPublishedBooks:31,numberOfPublishedChapters:314,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2632-0983",doi:"10.5772/intechopen.72877",isOpenForSubmission:!0},{id:"25",title:"Environmental Sciences",numberOfPublishedBooks:1,numberOfPublishedChapters:11,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2754-6713",doi:"10.5772/intechopen.100362",isOpenForSubmission:!0},{id:"10",title:"Physiology",numberOfPublishedBooks:11,numberOfPublishedChapters:141,numberOfOpenTopics:4,numberOfUpcomingTopics:0,issn:"2631-8261",doi:"10.5772/intechopen.72796",isOpenForSubmission:!0}],hsSeriesList:[{id:"3",title:"Dentistry",numberOfPublishedBooks:8,numberOfPublishedChapters:129,numberOfOpenTopics:2,numberOfUpcomingTopics:0,issn:"2631-6218",doi:"10.5772/intechopen.71199",isOpenForSubmission:!0},{id:"6",title:"Infectious Diseases",numberOfPublishedBooks:13,numberOfPublishedChapters:113,numberOfOpenTopics:3,numberOfUpcomingTopics:1,issn:"2631-6188",doi:"10.5772/intechopen.71852",isOpenForSubmission:!0},{id:"13",title:"Veterinary Medicine and Science",numberOfPublishedBooks:11,numberOfPublishedChapters:105,numberOfOpenTopics:3,numberOfUpcomingTopics:0,issn:"2632-0517",doi:"10.5772/intechopen.73681",isOpenForSubmission:!0}],sshSeriesList:[{id:"22",title:"Business, Management and Economics",numberOfPublishedBooks:1,numberOfPublishedChapters:18,numberOfOpenTopics:2,numberOfUpcomingTopics:1,issn:"2753-894X",doi:"10.5772/intechopen.100359",isOpenForSubmission:!0},{id:"23",title:"Education and Human Development",numberOfPublishedBooks:0,numberOfPublishedChapters:5,numberOfOpenTopics:1,numberOfUpcomingTopics:1,issn:null,doi:"10.5772/intechopen.100360",isOpenForSubmission:!0},{id:"24",title:"Sustainable Development",numberOfPublishedBooks:0,numberOfPublishedChapters:14,numberOfOpenTopics:5,numberOfUpcomingTopics:0,issn:null,doi:"10.5772/intechopen.100361",isOpenForSubmission:!0}],testimonialsList:[{id:"13",text:"The collaboration with and support of the technical staff of IntechOpen is fantastic. The whole process of submitting an article and editing of the submitted article goes extremely smooth and fast, the number of reads and downloads of chapters is high, and the contributions are also frequently cited.",author:{id:"55578",name:"Antonio",surname:"Jurado-Navas",institutionString:null,profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRisIQAS/Profile_Picture_1626166543950",slug:"antonio-jurado-navas",institution:{id:"720",name:"University of Malaga",country:{id:null,name:"Spain"}}}},{id:"6",text:"It is great to work with the IntechOpen to produce a worthwhile collection of research that also becomes a great educational resource and guide for future research endeavors.",author:{id:"259298",name:"Edward",surname:"Narayan",institutionString:null,profilePictureURL:"https://mts.intechopen.com/storage/users/259298/images/system/259298.jpeg",slug:"edward-narayan",institution:{id:"3",name:"University of Queensland",country:{id:null,name:"Australia"}}}}]},series:{item:{id:"24",title:"Sustainable Development",doi:"10.5772/intechopen.100361",issn:null,scope:"
\r\n\tTransforming our World: the 2030 Agenda for Sustainable Development endorsed by United Nations and 193 Member States, came into effect on Jan 1, 2016, to guide decision making and actions to the year 2030 and beyond. Central to this Agenda are 17 Goals, 169 associated targets and over 230 indicators that are reviewed annually. The vision envisaged in the implementation of the SDGs is centered on the five Ps: People, Planet, Prosperity, Peace and Partnership. This call for renewed focused efforts ensure we have a safe and healthy planet for current and future generations.
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\r\n\tThis Series focuses on covering research and applied research involving the five Ps through the following topics:
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\r\n\t1. Sustainable Economy and Fair Society that relates to SDG 1 on No Poverty, SDG 2 on Zero Hunger, SDG 8 on Decent Work and Economic Growth, SDG 10 on Reduced Inequalities, SDG 12 on Responsible Consumption and Production, and SDG 17 Partnership for the Goals
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\r\n\t2. Health and Wellbeing focusing on SDG 3 on Good Health and Wellbeing and SDG 6 on Clean Water and Sanitation
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\r\n\t3. Inclusivity and Social Equality involving SDG 4 on Quality Education, SDG 5 on Gender Equality, and SDG 16 on Peace, Justice and Strong Institutions
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\r\n\t4. Climate Change and Environmental Sustainability comprising SDG 13 on Climate Action, SDG 14 on Life Below Water, and SDG 15 on Life on Land
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\r\n\t5. Urban Planning and Environmental Management embracing SDG 7 on Affordable Clean Energy, SDG 9 on Industry, Innovation and Infrastructure, and SDG 11 on Sustainable Cities and Communities.
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\r\n\tThe series also seeks to support the use of cross cutting SDGs, as many of the goals listed above, targets and indicators are all interconnected to impact our lives and the decisions we make on a daily basis, making them impossible to tie to a single topic.
",coverUrl:"https://cdn.intechopen.com/series/covers/24.jpg",latestPublicationDate:"June 23rd, 2022",hasOnlineFirst:!0,numberOfPublishedBooks:0,editor:{id:"262440",title:"Prof.",name:"Usha",middleName:null,surname:"Iyer-Raniga",slug:"usha-iyer-raniga",fullName:"Usha Iyer-Raniga",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRYSXQA4/Profile_Picture_2022-02-28T13:55:36.jpeg",biography:"Usha Iyer-Raniga is a professor in the School of Property and Construction Management at RMIT University. Usha co-leads the One Planet Network’s Sustainable Buildings and Construction Programme (SBC), a United Nations 10 Year Framework of Programmes on Sustainable Consumption and Production (UN 10FYP SCP) aligned with Sustainable Development Goal 12. The work also directly impacts SDG 11 on Sustainable Cities and Communities. She completed her undergraduate degree as an architect before obtaining her Masters degree from Canada and her Doctorate in Australia. Usha has been a keynote speaker as well as an invited speaker at national and international conferences, seminars and workshops. Her teaching experience includes teaching in Asian countries. She has advised Austrade, APEC, national, state and local governments. She serves as a reviewer and a member of the scientific committee for national and international refereed journals and refereed conferences. She is on the editorial board for refereed journals and has worked on Special Issues. Usha has served and continues to serve on the Boards of several not-for-profit organisations and she has also served as panel judge for a number of awards including the Premiers Sustainability Award in Victoria and the International Green Gown Awards. Usha has published over 100 publications, including research and consulting reports. Her publications cover a wide range of scientific and technical research publications that include edited books, book chapters, refereed journals, refereed conference papers and reports for local, state and federal government clients. She has also produced podcasts for various organisations and participated in media interviews. She has received state, national and international funding worth over USD $25 million. Usha has been awarded the Quarterly Franklin Membership by London Journals Press (UK). Her biography has been included in the Marquis Who's Who in the World® 2018, 2016 (33rd Edition), along with approximately 55,000 of the most accomplished men and women from around the world, including luminaries as U.N. Secretary-General Ban Ki-moon. In 2017, Usha was awarded the Marquis Who’s Who Lifetime Achiever Award.",institutionString:null,institution:{name:"RMIT University",institutionURL:null,country:{name:"Australia"}}},editorTwo:null,editorThree:null},subseries:{paginationCount:5,paginationItems:[{id:"91",title:"Sustainable Economy and Fair Society",coverUrl:"https://cdn.intechopen.com/series_topics/covers/91.jpg",isOpenForSubmission:!0,annualVolume:11975,editor:{id:"181603",title:"Dr.",name:"Antonella",middleName:null,surname:"Petrillo",slug:"antonella-petrillo",fullName:"Antonella Petrillo",profilePictureURL:"https://mts.intechopen.com/storage/users/181603/images/system/181603.jpg",biography:"Antonella Petrillo is a Professor at the Department of Engineering of the University of Naples “Parthenope”, Italy. She received her Ph.D. in Mechanical Engineering from the University of Cassino. Her research interests include multi-criteria decision analysis, industrial plant, logistics, manufacturing and safety. She serves as an Associate Editor for the International Journal of the Analytic Hierarchy Process. She is a member of AHP Academy and a member of several editorial boards. She has over 160 Scientific Publications in International Journals and Conferences and she is the author of 5 books on Innovation and Decision Making in Industrial Applications and Engineering.",institutionString:null,institution:{name:"Parthenope University of Naples",institutionURL:null,country:{name:"Italy"}}},editorTwo:null,editorThree:null},{id:"92",title:"Health and Wellbeing",coverUrl:"https://cdn.intechopen.com/series_topics/covers/92.jpg",isOpenForSubmission:!0,annualVolume:11976,editor:{id:"348225",title:"Prof.",name:"Ann",middleName:null,surname:"Hemingway",slug:"ann-hemingway",fullName:"Ann Hemingway",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y000035LZFoQAO/Profile_Picture_2022-04-11T14:55:40.jpg",biography:"Professor Hemingway is a public health researcher, Bournemouth University, undertaking international and UK research focused on reducing inequalities in health outcomes for marginalised and excluded populations and more recently focused on equine assisted interventions.",institutionString:null,institution:{name:"Bournemouth University",institutionURL:null,country:{name:"United Kingdom"}}},editorTwo:null,editorThree:null},{id:"93",title:"Inclusivity and Social Equity",coverUrl:"https://cdn.intechopen.com/series_topics/covers/93.jpg",isOpenForSubmission:!0,annualVolume:11977,editor:{id:"210060",title:"Prof. Dr.",name:"Ebba",middleName:null,surname:"Ossiannilsson",slug:"ebba-ossiannilsson",fullName:"Ebba Ossiannilsson",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6LkBQAU/Profile_Picture_2022-02-28T13:31:48.png",biography:"Professor Dr. Ebba Ossiannilsson is an independent researcher, expert, consultant, quality auditor and influencer in the fields of open, flexible online and distance learning (OFDL) and the 'new normal'. Her focus is on quality, innovation, leadership, and personalised learning. She works primarily at the strategic and policy levels, both nationally and internationally, and with key international organisations. She is committed to promoting and improving OFDL in the context of SDG4 and the future of education. Ossiannilsson has more than 20 years of experience in her current field, but more than 40 years in the education sector. She works as a reviewer and expert for the European Commission and collaborates with the Joint Research Centre for Quality in Open Education. Ossiannilsson also collaborates with ITCILO and ICoBC (International Council on Badges and Credentials). She is a member of the ICDE Board of Directors and has previously served on the boards of EDEN and EUCEN. Ossiannilsson is a quality expert and reviewer for ICDE, EDEN and the EADTU. She chairs the ICDE OER Advocacy Committee and is a member of the ICDE Quality Network. She is regularly invited as a keynote speaker at conferences. She is a guest editor for several special issues and a member of the editorial board of several scientific journals. She has published more than 200 articles and is currently working on book projects in the field of OFDL. Ossiannilsson is a visiting professor at several international universities and was recently appointed Professor and Research Fellow at Victoria University of Wellington, NZ. Ossiannilsson has been awarded the following fellowships: EDEN Fellows, EDEN Council of Fellows, and Open Education Europe. She is a ICDE OER Ambassador, Open Education Europe Ambassador, GIZ Ambassador for Quality in Digital Learning, and part of the Globe-Community of Digital Learning and Champion of SPARC Europe. On a national level, she is a quality developer at the Swedish Institute for Standards (SIS) and for ISO. She is a member of the Digital Skills and Jobs Coalition Sweden and Vice President of the Swedish Association for Distance Education. She is currently working on a government initiative on quality in distance education at the National Council for Higher Education. She holds a Ph.D. from the University of Oulu, Finland.",institutionString:"Swedish Association for Distance Education, Sweden",institution:null},editorTwo:null,editorThree:null},{id:"94",title:"Climate Change and Environmental Sustainability",coverUrl:"https://cdn.intechopen.com/series_topics/covers/94.jpg",isOpenForSubmission:!0,annualVolume:11978,editor:{id:"61855",title:"Dr.",name:"Yixin",middleName:null,surname:"Zhang",slug:"yixin-zhang",fullName:"Yixin Zhang",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYWJgQAO/Profile_Picture_2022-06-09T11:36:35.jpg",biography:"Professor Yixin Zhang is an aquatic ecologist with over 30 years of research and teaching experience in three continents (Asia, Europe, and North America) in Stream Ecology, Riparian Ecology, Urban Ecology, and Ecosystem Restoration and Aquatic Conservation, Human-Nature Interactions and Sustainability, Urbanization Impact on Aquatic Ecosystems. He got his Ph.D. in Animal Ecology at Umeå University in Sweden in 1998. He conducted postdoc research in stream ecology at the University of California at Santa Barbara in the USA. After that, he was a postdoc research fellow at the University of British Columbia in Canada to do research on large-scale stream experimental manipulation and watershed ecological survey in temperate rainforests of BC. He was a faculty member at the University of Hong Kong to run ecological research projects on aquatic insects, fishes, and newts in Tropical Asian streams. He also conducted research in streams, rivers, and caves in Texas, USA, to study the ecology of macroinvertebrates, big-claw river shrimp, fish, turtles, and bats. Current research interests include trophic flows across ecosystems; watershed impacts of land-use change on biodiversity and ecosystem functioning; ecological civilization and water resource management; urban ecology and urban/rural sustainable development.",institutionString:null,institution:{name:"Soochow University",institutionURL:null,country:{name:"China"}}},editorTwo:null,editorThree:null},{id:"95",title:"Urban Planning and Environmental Management",coverUrl:"https://cdn.intechopen.com/series_topics/covers/95.jpg",isOpenForSubmission:!0,annualVolume:11979,editor:{id:"181079",title:"Dr.",name:"Christoph",middleName:null,surname:"Lüthi",slug:"christoph-luthi",fullName:"Christoph Lüthi",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRHSqQAO/Profile_Picture_2022-04-12T15:51:33.png",biography:"Dr. Christoph Lüthi is an urban infrastructure planner with over 25 years of experience in planning and design of urban infrastructure in middle and low-income countries. 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\r\n\tThe environment is subject to severe anthropic effects. Among them are those associated with pollution, resource extraction and overexploitation, loss of biodiversity, soil degradation, disorderly land occupation and planning, and many others. These anthropic effects could potentially be caused by any inadequate management of the environment. However, ecosystems have a resilience that makes them react to disturbances which mitigate the negative effects. It is critical to understand how ecosystems, natural and anthropized, including urban environments, respond to actions that have a negative influence and how they are managed. It is also important to establish when the limits marked by the resilience and the breaking point are achieved and when no return is possible. The main focus for the chapters is to cover the subjects such as understanding how the environment resilience works, the mechanisms involved, and how to manage them in order to improve our interactions with the environment and promote the use of adequate management practices such as those outlined in the United Nations’ Sustainable Development Goals.
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\r\n\tIn general, the harsher the environmental conditions in an ecosystem, the lower the biodiversity. Changes in the environment caused by human activity accelerate the impoverishment of biodiversity.
\r\n
\r\n\tBiodiversity refers to “the variability of living organisms from any source, including terrestrial, marine and other aquatic ecosystems and the ecological complexes of which they are part; it includes diversity within each species, between species, and that of ecosystems”.
\r\n
\r\n\tBiodiversity provides food security and constitutes a gene pool for biotechnology, especially in the field of agriculture and medicine, and promotes the development of ecotourism.
\r\n
\r\n\tCurrently, biologists admit that we are witnessing the first phases of the seventh mass extinction caused by human intervention. It is estimated that the current rate of extinction is between a hundred and a thousand times faster than it was when man first appeared. The disappearance of species is caused not only by an accelerated rate of extinction, but also by a decrease in the rate of emergence of new species as human activities degrade the natural environment. The conservation of biological diversity is "a common concern of humanity" and an integral part of the development process. Its objectives are “the conservation of biological diversity, the sustainable use of its components, and the fair and equitable sharing of the benefits resulting from the use of genetic resources”.
\r\n
\r\n\tThe following are the main causes of biodiversity loss:
\r\n
\r\n\t• The destruction of natural habitats to expand urban and agricultural areas and to obtain timber, minerals and other natural resources.
\r\n
\r\n\t• The introduction of alien species into a habitat, whether intentionally or unintentionally which has an impact on the fauna and flora of the area, and as a result, they are reduced or become extinct.
\r\n
\r\n\t• Pollution from industrial and agricultural products, which devastate the fauna and flora, especially those in fresh water.
\r\n
\r\n\t• Global warming, which is seen as a threat to biological diversity, and will become increasingly important in the future.
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\r\n\tThe environment is subject to severe anthropic effects. Among them are those associated with pollution, resource extraction and overexploitation, loss of biodiversity, soil degradation, disorderly land occupation and planning, and many others. These anthropic effects could potentially be caused by any inadequate management of the environment. However, ecosystems have a resilience that makes them react to disturbances which mitigate the negative effects. It is critical to understand how ecosystems, natural and anthropized, including urban environments, respond to actions that have a negative influence and how they are managed. It is also important to establish when the limits marked by the resilience and the breaking point are achieved and when no return is possible. The main focus for the chapters is to cover the subjects such as understanding how the environment resilience works, the mechanisms involved, and how to manage them in order to improve our interactions with the environment and promote the use of adequate management practices such as those outlined in the United Nations’ Sustainable Development Goals.
\r\n\tPollution is caused by a wide variety of human activities and occurs in diverse forms, for example biological, chemical, et cetera. In recent years, significant efforts have been made to ensure that the environment is clean, that rigorous rules are implemented, and old laws are updated to reduce the risks towards humans and ecosystems. However, rapid industrialization and the need for more cultivable sources or habitable lands, for an increasing population, as well as fewer alternatives for waste disposal, make the pollution control tasks more challenging. Therefore, this topic will focus on assessing and managing environmental pollution. It will cover various subjects, including risk assessment due to the pollution of ecosystems, transport and fate of pollutants, restoration or remediation of polluted matrices, and efforts towards sustainable solutions to minimize environmental pollution.
\r\n\tWater is not only a crucial substance needed for biological life on Earth, but it is also a basic requirement for the existence and development of the human society. Owing to the importance of water to life on Earth, early researchers conducted numerous studies and analyses on the liquid form of water from the perspectives of chemistry, physics, earth science, and biology, and concluded that Earth is a "water polo". Water covers approximately 71% of Earth's surface. However, 97.2% of this water is seawater, 21.5% is icebergs and glaciers, and only 0.65% is freshwater that can be used directly by humans. As a result, the amount of water reserves available for human consumption is limited. The development, utilization, and protection of freshwater resources has become the focus of water science research for the continued improvement of human livelihoods and society.
\r\n
\r\n\tWater exists as solid, liquid, and gas within Earth’s atmosphere, lithosphere, and biosphere. Liquid water is used for a variety of purposes besides drinking, including power generation, ecology, landscaping, and shipping. Because water is involved in various environmental hydrological processes as well as numerous aspects of the economy and human society, the study of various phenomena in the hydrosphere, the laws governing their occurrence and development, the relationship between the hydrosphere and other spheres of Earth, and the relationship between water and social development, are all part of water science. Knowledge systems for water science are improving continuously. Water science has become a specialized field concerned with the identification of its physical, chemical, and biological properties. In addition, it reveals the laws of water distribution, movement, and circulation, and proposes methods and tools for water development, utilization, planning, management, and protection. Currently, the field of water science covers research related to topics such as hydrology, water resources and water environment. It also includes research on water related issues such as safety, engineering, economy, law, culture, information, and education.
",coverUrl:"https://cdn.intechopen.com/series_topics/covers/41.jpg",keywords:"Water, Water resources, Freshwater, Hydrological processes, Utilization, Protection"}],annualVolumeBook:{},thematicCollection:[],selectedSeries:null,selectedSubseries:null},seriesLanding:{item:{id:"11",title:"Biochemistry",doi:"10.5772/intechopen.72877",issn:"2632-0983",scope:"Biochemistry, the study of chemical transformations occurring within living organisms, impacts all areas of life sciences, from molecular crystallography and genetics to ecology, medicine, and population biology. Biochemistry examines macromolecules - proteins, nucleic acids, carbohydrates, and lipids – and their building blocks, structures, functions, and interactions. 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. This Biochemistry Series will address the current research on biomolecules and the emerging trends with great promise.",coverUrl:"https://cdn.intechopen.com/series/covers/11.jpg",latestPublicationDate:"June 24th, 2022",hasOnlineFirst:!0,numberOfOpenTopics:4,numberOfPublishedChapters:314,numberOfPublishedBooks:31,editor:{id:"31610",title:"Dr.",name:"Miroslav",middleName:null,surname:"Blumenberg",fullName:"Miroslav Blumenberg",profilePictureURL:"https://mts.intechopen.com/storage/users/31610/images/system/31610.jpg",biography:"Miroslav Blumenberg, Ph.D., was born in Subotica and received his BSc in Belgrade, Yugoslavia. He completed his Ph.D. at MIT in Organic Chemistry; he followed up his Ph.D. with two postdoctoral study periods at Stanford University. Since 1983, he has been a faculty member of the RO Perelman Department of Dermatology, NYU School of Medicine, where he is codirector of a training grant in cutaneous biology. 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. He has published more than 100 peer-reviewed research articles and graduated numerous Ph.D. and postdoctoral students.",institutionString:null,institution:{name:"New York University Langone Medical Center",institutionURL:null,country:{name:"United States of America"}}},subseries:[{id:"14",title:"Cell and Molecular Biology",keywords:"Omics (Transcriptomics; Proteomics; Metabolomics), Molecular Biology, Cell Biology, Signal Transduction and Regulation, Cell Growth and Differentiation, Apoptosis, Necroptosis, Ferroptosis, Autophagy, Cell Cycle, Macromolecules and Complexes, Gene Expression",scope:"The Cell and Molecular Biology topic within the IntechOpen Biochemistry Series aims to rapidly publish contributions on all aspects of cell and molecular biology, including aspects related to biochemical and genetic research (not only in humans but all living beings). We encourage the submission of manuscripts that provide novel and mechanistic insights that report significant advances in the fields. Topics include, but are not limited to: Advanced techniques of cellular and molecular biology (Molecular methodologies, imaging techniques, and bioinformatics); Biological activities at the molecular level; Biological processes of cell functions, cell division, senescence, maintenance, and cell death; Biomolecules interactions; Cancer; Cell biology; Chemical biology; Computational biology; Cytochemistry; Developmental biology; Disease mechanisms and therapeutics; DNA, and RNA metabolism; Gene functions, genetics, and genomics; Genetics; Immunology; Medical microbiology; Molecular biology; Molecular genetics; Molecular processes of cell and organelle dynamics; Neuroscience; Protein biosynthesis, degradation, and functions; Regulation of molecular interactions in a cell; Signalling networks and system biology; Structural biology; Virology and microbiology.",annualVolume:11410,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/14.jpg",editor:{id:"165627",title:"Dr.",name:"Rosa María",middleName:null,surname:"Martínez-Espinosa",fullName:"Rosa María Martínez-Espinosa",profilePictureURL:"https://mts.intechopen.com/storage/users/165627/images/system/165627.jpeg",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",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",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",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",keywords:"Phenolic Compounds, Essential Oils, Modification of Biomolecules, Glycobiology, Combinatorial Chemistry, Therapeutic peptides, Enzyme Inhibitors",scope:"Chemical biology spans the fields of chemistry and biology involving the application of biological and chemical molecules and techniques. In recent years, the application of chemistry to biological molecules has gained significant interest in medicinal and pharmacological studies. This topic will be devoted to understanding the interplay between biomolecules and chemical compounds, their structure and function, and their potential applications in related fields. Being a part of the biochemistry discipline, the ideas and concepts that have emerged from Chemical Biology have affected other related areas. This topic will closely deal with all emerging trends in this discipline.",annualVolume:11411,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/15.jpg",editor:{id:"441442",title:"Dr.",name:"Şükrü",middleName:null,surname:"Beydemir",fullName:"Şükrü Beydemir",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0033Y00003GsUoIQAV/Profile_Picture_1634557147521",institutionString:null,institution:{name:"Anadolu University",institutionURL:null,country:{name:"Turkey"}}},editorTwo:{id:"13652",title:"Prof.",name:"Deniz",middleName:null,surname:"Ekinci",fullName:"Deniz Ekinci",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002aYLT1QAO/Profile_Picture_1634557223079",institutionString:null,institution:{name:"Ondokuz Mayıs University",institutionURL:null,country:{name:"Turkey"}}},editorThree:null,editorialBoard:[{id:"241413",title:"Dr.",name:"Azhar",middleName:null,surname:"Rasul",fullName:"Azhar Rasul",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRT1oQAG/Profile_Picture_1635251978933",institutionString:null,institution:{name:"Government College University, Faisalabad",institutionURL:null,country:{name:"Pakistan"}}},{id:"178316",title:"Ph.D.",name:"Sergey",middleName:null,surname:"Sedykh",fullName:"Sergey Sedykh",profilePictureURL:"https://mts.intechopen.com/storage/users/178316/images/system/178316.jfif",institutionString:null,institution:{name:"Novosibirsk State University",institutionURL:null,country:{name:"Russia"}}}]},{id:"17",title:"Metabolism",keywords:"Biomolecules Metabolism, Energy Metabolism, Metabolic Pathways, Key Metabolic Enzymes, Metabolic Adaptation",scope:"Metabolism is frequently defined in biochemistry textbooks as the overall process that allows living systems to acquire and use the free energy they need for their vital functions or the chemical processes that occur within a living organism to maintain life. Behind these definitions are hidden all the aspects of normal and pathological functioning of all processes that the topic ‘Metabolism’ will cover within the Biochemistry Series. Thus all studies on metabolism will be considered for publication.",annualVolume:11413,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/17.jpg",editor:{id:"138626",title:"Dr.",name:"Yannis",middleName:null,surname:"Karamanos",fullName:"Yannis Karamanos",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002g6Jv2QAE/Profile_Picture_1629356660984",institutionString:null,institution:{name:"Artois University",institutionURL:null,country:{name:"France"}}},editorTwo:null,editorThree:null,editorialBoard:[{id:"243049",title:"Dr.",name:"Anca",middleName:null,surname:"Pantea Stoian",fullName:"Anca Pantea Stoian",profilePictureURL:"https://mts.intechopen.com/storage/users/243049/images/system/243049.jpg",institutionString:null,institution:{name:"Carol Davila University of Medicine and Pharmacy",institutionURL:null,country:{name:"Romania"}}},{id:"203824",title:"Dr.",name:"Attilio",middleName:null,surname:"Rigotti",fullName:"Attilio Rigotti",profilePictureURL:"//cdnintech.com/web/frontend/www/assets/author.svg",institutionString:null,institution:{name:"Pontifical Catholic University of Chile",institutionURL:null,country:{name:"Chile"}}},{id:"300470",title:"Dr.",name:"Yanfei (Jacob)",middleName:null,surname:"Qi",fullName:"Yanfei (Jacob) Qi",profilePictureURL:"https://mts.intechopen.com/storage/users/300470/images/system/300470.jpg",institutionString:null,institution:{name:"Centenary Institute of Cancer Medicine and Cell Biology",institutionURL:null,country:{name:"Australia"}}}]},{id:"18",title:"Proteomics",keywords:"Mono- and Two-Dimensional Gel Electrophoresis (1-and 2-DE), Liquid Chromatography (LC), Mass Spectrometry/Tandem Mass Spectrometry (MS; MS/MS), Proteins",scope:"With the recognition that the human genome cannot provide answers to the etiology of a disorder, changes in the proteins expressed by a genome became a focus in research. Thus proteomics, an area of research that detects all protein forms expressed in an organism, including splice isoforms and post-translational modifications, is more suitable than genomics for a comprehensive understanding of the biochemical processes that govern life. The most common proteomics applications are currently in the clinical field for the identification, in a variety of biological matrices, of biomarkers for diagnosis and therapeutic intervention of disorders. From the comparison of proteomic profiles of control and disease or different physiological states, which may emerge, changes in protein expression can provide new insights into the roles played by some proteins in human pathologies. Understanding how proteins function and interact with each other is another goal of proteomics that makes this approach even more intriguing. Specialized technology and expertise are required to assess the proteome of any biological sample. Currently, proteomics relies mainly on mass spectrometry (MS) combined with electrophoretic (1 or 2-DE-MS) and/or chromatographic techniques (LC-MS/MS). MS is an excellent tool that has gained popularity in proteomics because of its ability to gather a complex body of information such as cataloging protein expression, identifying protein modification sites, and defining protein interactions. The Proteomics topic aims to attract contributions on all aspects of MS-based proteomics that, by pushing the boundaries of MS capabilities, may address biological problems that have not been resolved yet.",annualVolume:11414,isOpenForSubmission:!0,coverUrl:"https://cdn.intechopen.com/series_topics/covers/18.jpg",editor:{id:"200689",title:"Prof.",name:"Paolo",middleName:null,surname:"Iadarola",fullName:"Paolo Iadarola",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bSCl8QAG/Profile_Picture_1623568118342",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorTwo:{id:"201414",title:"Dr.",name:"Simona",middleName:null,surname:"Viglio",fullName:"Simona Viglio",profilePictureURL:"https://s3.us-east-1.amazonaws.com/intech-files/0030O00002bRKDHQA4/Profile_Picture_1630402531487",institutionString:null,institution:{name:"University of Pavia",institutionURL:null,country:{name:"Italy"}}},editorThree:null,editorialBoard:[{id:"72288",title:"Dr.",name:"Arli Aditya",middleName:null,surname:"Parikesit",fullName:"Arli Aditya Parikesit",profilePictureURL:"https://mts.intechopen.com/storage/users/72288/images/system/72288.jpg",institutionString:null,institution:{name:"Indonesia International Institute for Life Sciences",institutionURL:null,country:{name:"Indonesia"}}},{id:"40928",title:"Dr.",name:"Cesar",middleName:null,surname:"Lopez-Camarillo",fullName:"Cesar Lopez-Camarillo",profilePictureURL:"https://mts.intechopen.com/storage/users/40928/images/3884_n.png",institutionString:null,institution:{name:"Universidad Autónoma de la Ciudad de México",institutionURL:null,country:{name:"Mexico"}}},{id:"81926",title:"Dr.",name:"Shymaa",middleName:null,surname:"Enany",fullName:"Shymaa Enany",profilePictureURL:"https://mts.intechopen.com/storage/users/81926/images/system/81926.png",institutionString:"Suez Canal University",institution:{name:"Suez Canal University",institutionURL:null,country:{name:"Egypt"}}}]}]}},libraryRecommendation:{success:null,errors:{},institutions:[]},route:{name:"chapter.detail",path:"/chapters/24567",hash:"",query:{},params:{id:"24567"},fullPath:"/chapters/24567",meta:{},from:{name:null,path:"/",hash:"",query:{},params:{},fullPath:"/",meta:{}}}},function(){var e;(e=document.currentScript||document.scripts[document.scripts.length-1]).parentNode.removeChild(e)}()