Oxidoreductases in glycolysis, lactate fermentation and Krebs cycle.
\r\n\tComputational fluid dynamics is composed of turbulence and modeling, turbulent heat transfer, fluid-solid interaction, chemical reactions and combustion, the finite volume method for unsteady flows, sports engineering problem and simulations - Aerodynamics, fluid dynamics, biomechanics, blood flow.
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Dr. Bhattacharyya completed his Ph.D. in Mechanical Engineering from Jadavpur University, Kolkata, India and with the collaboration of Duesseldorf University of Applied Sciences, Germany. He received his Master’s degree from the Indian Institute of Engineering, Science and Technology, India (Formerly known as Bengal Engineering and Science University), on Heat-Power Engineering.\nHis research interest lies in computational fluid dynamics in fluid flow and heat transfer, specializing on laminar, turbulent, transition, steady, unsteady separated flows and convective heat transfer, experimental heat transfer enhancement, solar energy and renewable energy. He is the author and co-author of 107 papers in high ranked journals and prestigious conference proceedings. He has bagged the best paper award in a number of international conferences as well. 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It arises from genetic and environmental interactions that cause the deregulation of signaling pathways involved in fundamental cellular processes. Being a heterogeneous disease with multiple etiologies, cancer shows different pathological evolutions and treatment approaches [2]. Renal Cell Carcinoma (RCC) and Prostate Cancer (PCa) represent the most lethal and common urological cancers, respectively [1].
Kidney cancer represents 403,000 new cases and 175,000 deaths worldwide, with RCC accounting for 90% of these cases [1]. Because of kidney’s anatomic location, these tumors only become symptomatic in the late stages of the disease. Even though about 60% of RCCs are incidentally detected in an early stage because of routine imaging, about 30% are still diagnosed at the symptomatic phase, which is usually associated with worse prognosis [3]. Additionally, most of the patients continue to be diagnosed with locally advanced disease, with about 17% of them presenting distant metastasis at the diagnosis [4]. Apart from these, approximately 40% of patients submitted to surgery with curative intent will also relapse in a 5-year period [5]. Because of its radio and chemo-resistance, targeted therapies are the only agents available to manage metastatic patients, but one fourth of the patients never respond to them, and the ones who do, typically develop resistance in a median of 5–11 months of treatment [6].
On the other hand, with a world estimate of 1.2 million cases and more than 350 thousand deaths in 2018, PCa is the second most frequent cancer in men and the fifth cause of death [1]. Its treatment depends on the grade, stage and age of the patients, being the androgen deprivation therapy (ADT) one of the main therapy options because of its high dependence on the androgen pathway [7]. Despite the initial high response rates, nearly all men that undergo ADT develop resistance within 2 to 3 years, progressing to Castration Resistant PCa (CRPC) [8]. In the last few years new drugs came up as alternatives to these patients, but they present limited time benefits and patients eventually relapse [9].
The late diagnosis, the lack of accurate prognosis and disease follow up biomarkers, as well as the resistance to the existing therapies are some of the major current challenges in both prostate and renal cell carcinoma [10, 11]. Thus, there is an urgent need of more accurate and sensitive biomarkers as well as alternative therapeutic approaches in these tumor models.
Almost 10 years ago, in 2011, the reprogramming of energy metabolism was considered a hallmark of cancer and in the last few years the scientific community has devoted their time to better understand it in order to develop new therapeutic approaches and biomarkers [2]. Oxidoreductases (enzymes that catalyze electrons transfer from one molecule to another) play an important part in these deregulations since they are present in the different pathways involved in cells metabolism, namely in glucose’s metabolism [12].
Glucose, as one of the major “fuels” of any cell, has its metabolism altered in most tumor models [13]. However, because cancer is a heterogeneous disease, this deregulation depends on the type of cells that the tumor arises from, being RCC and PCa a good example of such differences.
RCC is a heterogeneous group of cancers with different genetic and molecular alterations, and histological and clinical characteristics [14]. Clear cell RCC (ccRCC) accounts for about 80% of RCC cases and the most common genetic event involved in its beginning is the copy number deletion, inactivating mutation and/or epigenetic silencing of
This is the most likely cause of the well-known Warburg Effect which is widely documented in ccRCC [17, 18]. The Warburg Effect, or aerobic glycolysis, was firstly described in 1920 by Otto Warburg and describes cancer cells’ preference to metabolize glucose through glycolysis followed by lactate fermentation instead of oxidative phosphorylation, even in the presence of oxygen (Figure 1) [19]. Very common in many tumors, there are several possible explanations to why cancer cells undergo these alterations, even though the energy resulting from it is significantly lower when compared to oxidative phosphorylation. Using aerobic glycolysis, cancer cells are able to obtain ATP in a faster way and this pathway supports better their high biosynthetic needs [18]. Moreover, the consequent acidification of the microenvironment due to the lactate fermentation is of great advantage to cancer cells since it has been shown to boost their invasiveness and metastatic capacity as well as to inhibit immune rejection [20, 21].
RCC’s glucose metabolic switch. In RCC cells, pyruvate is transformed in lactate, with the production of ATP instead of undergoing Krebs cycle and oxidative phosphorylation (Warburg effect). Created by
In ccRCC, besides
In addition to thar, the deregulation of the expression of several enzymes involved in the glucose metabolic pathways has already been reported in ccRCC, including several oxidoreductases, such as glyceraldehyde-3-phosphate dehydrogenase (G3PD), lactate dehydrogenase (LDHA) which belong to the glycolysis pathway; pyruvate dehydrogenase (PD) and isocitrate dehydrogenase (IDH) involved in the Krebs Cycle and succinate dehydrogenase (SDH) which is part of the oxidative phosphorylation pathway [16, 23, 24, 25, 26].
Due to its organ’s function, prostatic tissue shows a unique metabolic activity under normal conditions, which will reflect in the disruptions presented by its cancer cells. One of the key functions of the prostate gland is to produce large amounts of citrate that is secreted as part of the seminal liquid [27]. Thus, normal prostate epithelial cells undergo a very inefficient energy metabolism.
In most organs, glucose is metabolized through glycolysis in pyruvate, which is decarboxylated in the mitochondria to generate Acetyl-CoA. This metabolite reacts with oxalocetate to generate citrate which is oxidized and undergoes the Krebs Cycle where a large amount of NADH is produced (that will be used in oxidative phosphorylation to produce ATP), as well as precursors of several amino acids [28]. In normal prostate epithelial cells, there is an impairment of the mitochondrial aconitase, responsible for citrate oxidization, granting this metabolite accumulation, which is needed in the seminal liquid composition [27]. Aconitase’s inhibition is triggered by an accumulation of zinc in these cells due to the overexpression of the zinc-regulated transporter/iron-regulated transporter-like protein 1 (ZIP1) [29]. Thus, in these cells, citrate is the final product of glucose metabolism and oxaloacetic acid (which normally is regenerated in the Krebs cycle) is produced through aspartate imported from the plasma through a specific carrier [30]. Because of Krebs cycle inhibition, and consequent oxidative phosphorylation impairment, these cells show a higher glycolytic rate [28].
Prostate cancer cells, however, have increased energy demands. Franklin and Costello have concluded that an early event in PCa carcinogenesis is the completion of the Krebs cycle and subsequent ability to produce much more ATP [31]. In fact, PCa cells show dramatically reduced levels of zinc, and consequent reactivation of m-aconitase and of Krebs cycle [32]. Interestingly, zinc has also been shown to induce apoptosis and inhibit invasion and angiogenesis in PCa cells [33, 34].
Nevertheless, it is important to take into consideration that cells need to readjust their bioenergetics and metabolism according to their energetic needs, during cancer progression. Thus, in its metastatic stage, PCa has been shown to switch to Warburg Effect [35]. The exact mechanisms behind this switch are not yet fully understood, but the microenvironment in the metastatic sites seems to play a key role, whether through the neighboring adipocytes or through the immune system. These seem to be able to increase HIF1α’s production inducing aerobic glycolysis and blocking oxidative phosphorylation (Figure 2) [36, 37].
PCa’s glucose metabolic switch. Normal prostate epithelial cells have the Krebs cycle interrupted because of their need to secrete citrate as part of seminal fluid. In prostate cancer, Krebs cycle is resumed because of the increased demand for energy. Warburg effect is only observed in the more advanced stages of the tumor. Created by
Several oxidoreductases involved in the glucose metabolic pathways have already been studied in PCa and reported as deregulated, such as glyceraldehyde-3-phosphate dehydrogenase (G3PD) and lactate dehydrogenase (LDHA) which belong to the glycolysis pathway and pyruvate dehydrogenase (PD) and isocitrate dehydrogenase (IDH) involved in the Krebs Cycle [38, 39, 40, 41].
The deregulation of the oxidoreductases as well as other enzymes involved in the glucose metabolism pathways is necessary for its reprogramming. This deregulation has already been connected with microRNAs (miRNAs), both in RCC and in PCa [18, 42].
miRNAs are short non-coding RNAs (~19 to 25 nucleotides) which regulate gene expression at a post-transcriptional level. Through binding to the 3′ untranslated region (3’ UTR) of mRNAs, miRNAs induce their degradation or translation repression [43]. These molecules are important modulators of cellular behavior being involved in different biological processes such as cell development, differentiation, apoptosis, proliferation, and metabolism. This is due to their dynamic expression since each miRNA regulates up to 100 different mRNAs and more than 10,000 mRNAs are regulated by miRNAs [44].
There are different characteristics that make miRNAs good biomarkers’ candidates. Firstly, miRNAs have different expression patterns in normal cells when compared with tumoral ones, and even among different subtypes or in different stages of the disease, which shows their potential as biomarkers’ candidates [45]. Secondly, there has been cumulating evidence regarding the fact that miRNAs are secreted into several body fluids, such as serum, plasma, saliva or urine [46]. Finally, miRNAs circulate in these fluids incorporated into protein complexes or extracellular vesicles, which protect them from RNAse degradation and make them resistant to extreme conditions like temperature or pH differences [47].
In fact, in previous studies circulating miRNAs profiles have already been associated with histology, staging and clinical endpoints, including patients’ survival and therapy response both in ccRCC and in PCa [48, 49, 50].
Thus, the study of miRNAs whose targets are involved in the glucose metabolism in tumor models such as RCC and PCa is highly important, not only because it can help to better understand the differences in metabolic deregulations of the different tumors, but also because this knowledge can be applied in designing new-targeted therapies and biomarkers.
This chapter is focused on the three main glycolytic pathways: glycolysis, Krebs cycle and Lactate Fermentation. Since oxidoreductases are present in these three pathways, we chose this type of enzymes to select miRNAs that directly regulate them (Table 1).
Following, we used miRTarBase (version 8.0), the largest known online database of validated miRNA:mRNA target interactions, to select the miRNAs that directly target these enzymes [51]. Only studies featuring hsa-miRNAs and functional miRNA Target Interaction (MTI) evidence were considered. The selected miRNAs and the respective validated targets are displayed in Figure 3.
miRNAs that directly regulate the oxidoreductases involved in the main pathways of glucose catabolism. Created by
A systematic search in Pubmed was then conducted regarding the existing evidence for each miRNA in both ccRCC and in PCa, in order to get a deeper knowledge of these miRNAs expression in these tumor models. To do so, we combined each miRNA with the following keywords: “renal cell carcinoma”, “RCC”, “Kidney Cancer”; “Prostate Cancer”. The obtained scientific papers were manually curated to determine the association between the miRNA and either RCC or PCa. The criteria of exclusion were the following: 1) scientific papers that do not report results from human samples; 2) scientific papers that do not directly correlate the miRNA with the disease. From the 56 papers initially found, 23 were excluded. For each selected paper, we extracted information regarding the deregulation of the miRNA’s expression in each tumor model (upregulated ↑/downregulated ↓) and gathered it in the following tables, according to the metabolic processes involved.
Glycolysis is the pathway responsible for converting glucose in pyruvate and it is constituted by a series of enzymatic reactions. Its sixth step is catalyzed by an oxidoreductase - Glyceraldehyde_3-phosphate_dehydrogenase (GAPDH) – responsible for transforming glyceraldehyde 3-phosphate in D-glycerate 1,3-biphosphate. According to miRTarBase (version 8.0), GAPDH is directly targeted by miR-29c-3p and miR-644a [51]. The studies regarding these miRNAs in both RCC and PCa are scarce, and miR-644a’s expression is still not described in RCC nor miR-29c-3p’s expression is described in PCa (Tables 2 and 3).
Glycolysis | Lactate fermentation | Krebs cycle |
---|---|---|
GAPDH | LDHA | PDH |
IDH | ||
KGDH | ||
SDH | ||
MDH |
Oxidoreductases in glycolysis, lactate fermentation and Krebs cycle.
Enzyme | miRNA | Sample type | Outcome | References |
---|---|---|---|---|
GAPDH | miR-29c-3p | Tissues and Cell lines | ↓ | [52] |
Deregulation of the miRNAs that directly target the glycolysis’ oxidoreductases in RCC.
Enzyme | miRNA | Sample type | Outcome | References |
---|---|---|---|---|
GAPDH | miR-644a | Tissues | ↓ | [53] |
Deregulation of the miRNAs that directly target the glycolysis’ oxidoreductases in PCa.
In both tumor models, the miRNAs targeting GAPDH are downregulated, which may partly explain the upregulation of GADPH already observed in PCa [52, 53]. There is, in fact, an increase of glucose consumption in cancer due to the bigger energetic needs of tumoral cells. Since glycolysis is the basis of glucose catabolism, either by following Krebs Cycle or Lactate Fermentation, the upregulation of the expression of this pathway’s enzymes will help ensure cancer cells’ catabolic demands.
Lactate fermentation is the metabolic process in which the pyruvate resulting from glycolysis is transformed in lactate with ATP production. This reaction is catalyzed by an oxidoreductase – Lactate Dehydrogenase (LDHA), whose mRNA, according to miRTarBase (version 8.0), is directly targeted by miR-34a-5p, miR-23a-3p, miR-24-3p, miR-210-3p, miR-374a-5p and miR-200b-3p [51]. To the best of our knowledge, there are still no studies regarding miR-24-3p and miR-374a-5p’s expression in RCC as well as miR-374a-5p’s expression in PCa. The studies regarding the other miRNA’s expression in RCC are summarized in Table 4 and the ones regarding miRNA’s expression in PCa are summarized in Table 5.
Enzyme | miRNA | Sample type | Outcome | References |
---|---|---|---|---|
LDHA | miR-34a-5p | Cell lines | ↑ | [54] |
Tissues and cell lines | ↑ | [55] | ||
Tissues | ↓ | [56] | ||
miR-23a-3p | Cell lines | ↓ | [57] | |
Tissues and cell lines | ↑ | [58] | ||
miR-210-3p | Tissues | ↑ | [59] | |
Cell lines | ↓ | [60] | ||
Cell lines | ↓ | [61] | ||
Tissues and urine | ⇅ | [62] | ||
Tissues | ↑ | [63] | ||
Tissues and urine | ⇅ | [64] | ||
Tissues | ↑ | [65] | ||
Cell lines and plasma | ↑ | [66] | ||
miR-200b-3p | Cell lines | ↓ | [67] |
Deregulation of the miRNAs that directly target the lactate Fermentation’s oxidoreductases in RCC.
Enzyme | miRNA | Sample type | Outcome | References |
---|---|---|---|---|
LDHA | miR-34a-5p | Cell lines (resistant vs. hormonal sensitive) | ↓ | [68] |
Urinary exosomes and tissues | ↓ | [69] | ||
Cell lines | ↓ | [70] | ||
miR-23a-3p | Tissues | ↑ | [71] | |
miR-24-3p | Urine | ↓ | [72] | |
Urine | ↓ | [73] | ||
Tissues and cell lines | ↓ | [74] | ||
miR-210-3p | Tissues | ↑ | [75] | |
Tissues | ↑ | [76] | ||
miR-200b-3p | Tissues | ↑ | [77] | |
Cell lines | ↓ | [78] | ||
Metastatic tissues | ↓ | [79] | ||
Chemo-resistant cells | ↑ | [80] |
Deregulation of the miRNAs that directly target the lactate fermentation’s oxidoreductases in PCa.
In RCC, the available studies for the selected miRNAs are controversial. This may be result of lack of standardized procedures but also of the different types of samples analyzed. Moreover, it is interesting to look at the studies of miR-210-3p’s expression. This miRNA was significantly increased in ccRCC patients at the time of surgery, when compared to healthy donors, but significantly decreased in follow-up disease-free ccRCC patients of the same cohort [62, 64]. These studies show, not only this miRNA potential as follow-up biomarker but are also an example of miRNAs dynamic expression. In PCa, one can notice that hormonal resistant and metastatic PCa show a decrease in miR-34a-5p and miR-200b-3p, which may traduce in an increase of LDHA and the switch to Warburg Effect which is only observed in these stages of PCa [68, 79].
Krebs Cycle, also known as the tricarboxylic acid cycle, follows glycolysis in the glucose catabolism when oxygen is present. It is preceded by the transformation of pyruvate in acetyl-coA, which will enter the cycle – a series of reactions that provide precursors of amino acids as well as the reducing agent NADH which will be used in the oxidative phosphorylation pathway and lead to ATP production.
Pyruvate oxidation in acetyl-coA is catalyzed by an oxidoreductase – Pyruvate dehydrogenase (PDH), whose mRNA is, according to miRTarBase (version 8.0) directly targeted by miR-96-3p [51]. However, there are still no studies regarding this miRNA in both RCC and in PCa.
In the series of reactions of Krebs Cycle, there are 4 reactions catalyzed by 4 oxidoreductases – Isocitrate dehydrogenase (IDH), α-ketoglutarate dehydrogenase (KDGH), Succinate dehydrogenase (SDH) and Malate dehydrogenase (MDH). According to miRTarBase (version 8.0), miRNAs directly targeting KDGH and MDH were not yet identified. Moreover, SDH is directly targeted by miR-31-3p, which, to the best of our knowledge, has not yet been studied in RCC and in PCa [51].
IDH is directly targeted by miR-30c-5p. There are few studies regarding this miRNA both in RCC (Table 6) and in PCa (Table 7).
Deregulation of the miRNAs that directly target the Krebs cycle’s oxidoreductases in RCC.
Deregulation of the miRNAs that directly target the Krebs Cycle’s oxidoreductases in PCa.
In these studies, the expression of miR-30c-5p in RCC is downregulated which would suggest an upregulation of IDH’s mRNA expression. However, this protein was shown to be downregulated in this tumor model [85]. In fact, a single mRNA can be regulate by several miRNAs, making the miRNA:mRNA expression not always inversely correlated. Nevertheless, the fact that miR-30-c-5p was downregulated in urinary exosomes shows its potential as a biomarker in a liquid biopsy approach [81].
In PCa the results regarding this miRNA are scarce and controversial, showing the need of more studies to clarify its expression levels.
miRNAs potential in the oncology field has been widely recognized and there has been an increase of studies regarding their deregulation in cancer in the last few years. However, there are many genes whose mRNA have not been identified as direct targets of any miRNA. In this book chapter, both KGDH and MDH, key enzymes in the Krebs Cycle, have not been directly associated with any miRNAs. Moreover, there are several miRNAs that directly target the mRNA of key enzymes of glucose catabolism but have not yet been studied in RCC (miR-644a, miR-24-3p, miR-374a-5p, miR-96-3p and miR-31-3p) and in PCa (miR-29c-3p, miR-374a-5p, miR96-3p, miR-31-3p). Additionally, some miRNAs present controversial results which shall be subject of more studies to confirm their deregulation. Nevertheless, two miRNAs have been identified as downregulated (miR-29c-3p and miR-200b-2p) in RCC and three miRNAs have been identified as downregulated (miR-644a, miR-34a-5p and miR-24-3p) and two as upregulated (miR-23a-3p and miR-210-3p) in PCa. Their potential as biomarkers of both RCC and PCa could be increased if combined as a profile, which could pose as an advance to establish a successful liquid biopsy approach.
Because of their influence in their target genes’ expression, the reestablishment of miRNAs’ levels may have a great impact in the regulation of glucose metabolism. Restoring the levels of the downregulated miRNAs in both RCC and PCa could benefit the current cancer therapies and one possible way to do so is through a nanomedicine approach. Nanoparticles (NPs) are small organized structures with sizes between in size 1 and 100 nm that show very specific chemical and physical properties due to their size and composition [86]. Even though the existing research is scarce, NPs can improve the specificity of miRNAs delivery to target cells (thus reducing side effects) and allow for controlled miRNA release [87]. They also can protect them from degradation and prevent their clearance by the reticuloendothelial system. Moreover, they avoid unfavorable immune cell stimulation [87]. NPs highly depend on their capping which acts prevents their agglomeration and stops uncontrolled growth. The choice of capping will highly influence NPs properties. To effectively deliver the miRNAs selected in this chapter, a glucose capping could be an interesting choice. As stated above, both in RCC and PCa, tumoral cells show an increased glucose consumption when compared with their counterpart normal cells. Thus, glucose as NP’s capping could favor the selective delivery of miRNAs and would likely not be recognized as antagonist by the immune system.
The deregulation of glucose metabolism as a great influence in the pathophysiology of cancer, with the oxidoreductases involved in its pathways posing as both an opportunity to better comprehend the disease and finding not only strategies of detecting and monitoring it but also new therapeutic strategies. miRNAs could be part of these strategies since they influence the expression of these enzymes. Both in RCC and PCa, there are studies regarding miRNAs that target these oxidoreductases, showing their impact in patients’ prognosis. In the future, more studies are needed, regarding the identification of more miRNAs that target for example KGDH and MDH and their validation in RCC and PCa. Moreover, exploring the potential of glucose capped NPs carrying these miRNAs could help establish new therapeutic strategies that would benefit RCC and PCa management.
We would like to thank Liga Portuguesa Contra o Cancro – Núcleo Regional do Norte – LPCC-NRN (Portuguese League against Cancer). M.M. is a recipient of a research scholarship awarded by LPCC-NRN (Portuguese League against Cancer—Northern Branch). F.D. is a recipient of a research fellowship from the project NORTE-01-0247-FEDER-033399, supported by Norte Portugal regional Operational Program (NORTE 2020), under the PORTUGAL 2020 Partnership Agreement, through European Regional Development Fund (ERDF).
The authors declare no conflict of interest.
Living organisms interact with and adapt to the EMF environment. This discovery has ignited interest in the analysis of the EMF-biological systems [1, 2, 3, 4]. Researchers imagine that precise tuning of experimental and clinical REMFS exposure could lead to favorable health results including the development of treatment and diagnostic devices [5, 6]. REMFS exposures produce the activation of multiple biological pathways, including changes in Ca2+ regulation [7, 8], channel activity [9], enzyme activity [10], RNA and DNA synthesis [11, 12, 13], expression of microRNA [14, 15, 16], free radical processes in the genetic effects of EMF [17, 18, 19], decreasing oxidative stress [20, 21, 22, 23, 24], activation of the heat shock response [25], activation of the heat shock factor 1 (HSF1) [26], cytoprotecting [27], growth behavior [11, 28], activation of the ubiquitin-proteasome [29, 30, 31], autophagy-lysosome systems [32], inflammation [33, 34, 35], mitochondrial enhancement [36], neuronal activity [37], and a reduction in β-secretase activity [38].
Here, we will focus on studies performed on the REMFS spectrum (50–918 MHz) to explain the mechanism by which non-ionizing, non-thermal, non-modulated, continuous waves cause biological effects. We will use our and other researchers’ recent results on human cell cultures and mouse AD models to explain this interaction. Initially, the frequency used in our REMFS experiments was 50 MHz with a specific absorption rate (SAR) of 0.5 W/kg. We found that these exposures upregulated the heat shock factor-1 (HSF1) in human lymphocytes and mouse fibroblasts [39]. HSF1 upregulation increased 70-kDa heat shock protein (HSP70) levels and delayed cellular senescence and death in these cell cultures [39]. Our recent data [40] demonstrated that cultures treated with REMFS at 64 MHz, with a SAR of 0.6 W/kg for 1 h daily for 21 days, had significantly reduced (p = 0.001) levels of Aβ40 peptide, compared to untreated cultures [40]. We also demonstrated a quantitative reduction of Aβ levels in primary human neuron cultures after different times and power protocols. There are further therapeutic implications of REMFS based on the improved cognitive function noted by lowering of Aβ levels in several AD mouse model studies performed by other investigators using 918 MHz exposures [36, 37, 38, 41].
The aforementioned biological effects demonstrate that REMFS is a multi-target strategy with potentially therapeutic implications on human diseases. In fact, among the biological effects observed, results of our experiments promote the capacity of REMFS to influence various networks of physiological functions that are dysregulated in the aging process and in Late Onset Alzheimer’s disease (LOAD) [39, 40, 42].
The low energy (2–37 eV−7) of the REMFS exposures is not able to cause any chemical change under the provision of classical physics, since the atoms or molecules pass through a potential barrier that they theoretically cannot overcome [43]. Our main challenge is to explain the mechanism of the REMFS-biological system interaction. There is a disparity between the low energy carried by the REMFS perturbation and the response of the biological system. The REMFS biological system interaction is a paradox from the classical point of view as it enables elementary particles and atoms to penetrate an energetic barrier without the need for sufficient energy to overcome it. To solve this paradox we have to look into the quantum scale and examine non-classical physical phenomenon such as wave-particle duality and quantum tunneling [44].
Despite this difficulty here we will describe a plausible sequence of events and a mathematical model for the REMFS-interaction. First we need to consider the REMFS perturbation as a time dependent adiabatic perturbation of water (the most likely receptor for REMFS), specifically the H bond network of the interfacial water [45]. REMFS subjects the quantum system, in the form of the H bond, to gradually changing external conditions giving the quantum system sufficient time for the functional form to adapt [46]. The probabilities of quantum transitions of the adiabatic change in the frequency of the quantum system have been calculated previously on the example of the harmonic oscillator [47].
The reason for the REMFS biological effects rests on the difference between the man-made EMF, and the natural EMF [48]. Man-made EMF waves are produced by parallel EMF oscillating circuits, whereas natural electromagnetic radiation is produced by atomic events such as nuclear fusion from the sun releasing infrared, visible, ultraviolet, X-rays [48]. For this reason, man-made RF-EMF vibrations occur in a single plane, so they are polarized in contrast to the multi plane vibrations from the natural EMF waves. This polarization would explain the differences in the biological effects of man-made versus natural RF-EMF. The polarized RF-EMF exposure has the ability to force all charged/polar molecules and chemical bonds to oscillate on parallel planes, and in phase with the applied polarized field [48, 49]. This external excitatory oscillation forces the exposed physical or chemical system to vibrate at the excitatory frequency changing the frequency of the system to the excitatory frequency [50, 51]. One of the targets of this driven oscillation is the hydrogen bond (HB) network of the first layer of the interfacial water (FLIFW) that surrounds an RNA which in the case of REMFS is a long non-coding RNA (HSR1) [52, 53]. The REMFS oscillations are absorbed by the HB which then acts as a driven quantum harmonic oscillator [54]. This HB responds to REMFS increasing its vibration amplitude [55] with the consequent decreased distance in the direction of the nucleic acid [56]. Since the tunnel probability is proportional to the square of the amplitude, the tunneling probability is increased. REMFS induced quantum tunneling allows proton transfer from the interfacial water to the nucleic acids of RNA [57]. The protonation of the nucleic acid results in tautomeric interconversions [58] with the consequent conformational changes. In the case of the REMFS, a long non-coding RNA called Heat shock RNA (HSR1) changes from a close to an open structure [53] able to bind and activate HSF1 to initiate the expression of several heat shock proteins and chaperones including HSP70 [39].
We developed a mathematical model of the REMFS and biological systems interaction at the quantum level. We hypothesized the quantum effects of REMFS that explain how a low energy exposure is able to produce biochemical changes. For clarity, we divided them into 3 stages with the consequent three equations (see Figure 1).
REMFS quantum effects on the first layer of the interfacial water of the RNA. REMFS (repeated electromagnetic field stimulation).
Stage 1. The oscillating REMFS energy causes a time dependent adiabatic perturbation on the first layer of the interfacial water (FLIFW). REMFS perturbs the HB from FLIFW to the oxygen (O) of the “Guanine of the RNA” (GRNA). Under REMFS the H bond of the FLIFW acts as a driven quantum harmonic oscillator increasing the amplitude of the HB vibrations. The following equation estimates the increase in the amplitude of HB vibration when it acts as a driven quantum harmonic oscillator system under REMFS [59]. See following time dependent equation from Piilo et al. to find the amplitude change under REMFS:
We will obtain the change in the amplitude of the H bond vibration under REMFS:
Where A describes the amplitude and ω the oscillation frequency of the periodic force,
Stage 2. The increased HB vibration amplitude induced by REMFS triggers shortening of the HB of the FLIFW to O of the GRNA. The calculated distance between the H from the first layer of the interfacial water and the Oxygen of the RNA Oxygen is 1.85 Å [60]. This value is very short, predisposing the H for quantum tunneling. The following equation estimates the change in HB shortening as a function of the amplitude of the oscillation [61].
To find the variation of the HB distance we will use the equation from Samdal et al. using the average over the inter-nuclear configurations of the interfacial water and the RNA nucleic acids (
Fr(q) = variation of bond distance; P(q) = probability function.
The equation of P(q) in the classical Boltzmann approximation is:
This equation predicts the shortening of the HB of the interfacial water under the time dependent perturbation caused by REMFS.
Stage 3. Shortening of the H bond decreases distance from the H from the FLIFW to the O from the GRNA. This will increase the probability of proton tunneling. The following equation estimates the quantum tunneling probability when barrier thickness or distance decreases [43].
Where E is a particle of energy, U0 is the height of the barrier, and E < U0. Also where m is the mass, d is the thickness of the barrier, α is the attenuation factor.
These three equations formed the mathematical model that is able to predict how the time dependent perturbation caused by REMFS affects the HB network of the first layer of the interfacial water. This HB acts as a quantum harmonic oscillator to produce proton tunneling and the protonation of the nucleic acids of the surrounding RNA to produce biological effects.
Multiple studies have found that repeated mild heat-shock (RMHS) produce beneficial effects on human fibroblasts experiencing in vitro senescence [62]. This prompted our laboratory to study the effects of a similar electromagnetic stimuli but instead applying lower frequency energy and therefore less risk of producing heat damage (430 THz vs. 64 MHz). The fact that the energy of the REMFS exposures are several orders of magnitude lower energy that heat exposure, yet both heat and REMFS are able to activate the HSR, makes REMFS a more suitable and safer strategy to activate this biological pathway to prevent and treat age-related diseases. We hypothesized that these exposures would produce anti-aging changes such as delay of in vitro senescence, would also lead to retardation of progressive cell enlargement, prevention of development of abnormal proteins, increased glutathione, and decrease in age-dependent glycosylation [63], as well as maintenance of youthful morphology, increased proteasome activity, increased levels of various heat shock proteins (HSP’s), increased resistance against oxidative abilities, and UV-A irradiation similar to repeated mild heat shock [64]. Interestingly many of these anti-aging effects are produce by the heat shock response (HSR) elements [65]. In fact, attenuation in the HSR during senescence is the earliest event in the aging process, and is characterized by loss of proteostasis [66] that comes as a result of decreased heat shock factor-1 (HSF1) DNA-binding [67].
Originally our laboratory utilized a frequency of 50 MHz, a power of 0.5 W, and a specific absorption rate (SAR) of 0.6 W/kg to expose different types of cell cultures applying different dose regimes [39]. REMFS treated cell cultures showed anti-aging effects. The proposed mechanism is the activation of HSF1 when REMFS releases HSF1 from its repressor Hsp90 to activate it. This study suggests that EMF exposure directly interacts with the HSF1-Hsp90 complex, releasing HSF1 for activation preparing it for following injuries. Our experiments also revealed that REMFS increased the population doublings number and changed the morphology of the cells to youthful appearance near the end of their replicative life in wild type, but not in the knockout HSF1 cell cultures. REMSF also decreased cell mortality in human T-cells. Remarkably, REMFS also increased HSF1 phosphorylation, enhanced HSF1-DNA binding, and improved HSP70 expression relative to non-treated cells [39].
We hypothesized a mechanism in which REMFS oscillation produces increase amplitude of the hydrogen bond of the interfacial water, therefore increasing the probability of proton tunneling. This proton transfer between the hydrogen bond of the interfacial water and the oxygen of the adjacent nucleic acids of the heat-shock-RNA1 (HSR1) will protonate the nucleic acid to form tautomers [58] that will cause conformational changes in this long non-coding RNA [68]. This secondary structure would be able to bind HSF1 and activate it by dissociation from the repressor chaperone HSP90 [39]. Then, activated HSF1 enters the nucleus and binds DNA to induce expression of beneficial chaperones and, ultimately, the promotion of anti-aging and proteostasis effects [69]. The REMSF exposure utilized here is a potential new strategy to treat age-related diseases such as Alzheimer’s. We will examine the experiments from REMFS exposures in human neuronal cultures [40] and the studies from other investigators in AD mouse models [41].
One of the hallmarks of the aging process is the decrease of the proteostasis due to attenuation of the HSF1 which produce protein aggregation [42]. Alzheimer’s is the most common protein deposition disease, it is caused by beta amyloid (Aβ) aggregation. Our recent study showed that REMFS decreased Aβ levels in human neuronal cultures [40]. REMFS decreased Aβ 1–40 and Aβ 1–42 levels. Importantly, it did not cause any toxicity in the neuronal cultures. We tested several REMFS parameters such as time of exposure, frequency, etc. to define any change in the levels of Aβ. Initially we used REMFS treatments at 64 MHz with a SAR of 0.6 W/kg daily for 1 h for 21 days. Results showed a decrease of 58.3% in Aβ 1–40 levels. We also found that these treatments did not cause any toxicity to the cultures compared to control, non-treated cells as measured by LDH levels, cell morphology, cell attachment, cell number, or neurite extension. Subsequently, we decided to determine if 14 days of REMFS at 64 or 100 MHz with a lower SAR of 0.4 W/kg also decreased the Aβ 1–42 levels. We found that there was a similar significant difference in the Aβ 1–42 levels when we increased the exposure time from 1 to 2 h or when we put the chamber outside the incubator. When we increased the frequency from 64 to 100 MHz; we found a similar beneficial effect in Aβ 1–42 levels. This suggest that REMFS at 64 MHz with a SAR of 0.4 W/kg for 1 h could be the minimal energy required to induce reduction of the Aβ peptides levels, these results are important for future clinical trials. All these suggest that the decrease of Aβ levels in cell cultures were mediated by the activation of the proteostasis master regulator HSF1 [39], this activated HSF1 would increase the expression of chaperones to induce Aβ degradation.
The first REMFS study that prevented cognitive impairment in a transgenic (Tg) AD mouse model “Transgene with human APP gene bearing the Swedish mutation” (AβPPsw) was performed with a pulsed/modulated RF-EMF at 918 MHz which produced a SAR of 0.25–1.05 W/kg over a 7–9 month period [41]. Non-treated Tg mice showed cognitive impairment in memory tests, on the other hand treated Tg mice preserved memory after 6–7 months of REMFS treatment. A more recent REMFS experiment applying daily exposures for a two-month period in older Tg mice (21–27 months) showed improvement in the Y-maze task (memory test), though did not show improvement in more complex tests after 2 months of REMFS [36]. Also the old non-treated Tg had very high levels of Aβ deposition in most areas of the brain. Conversely, the EMF-treated Tg mice exhibited an impressive 24–30% removal of Aβ deposits, suggesting a disaggregation of pre-existing Aβ deposits following 2 months of daily EMF treatment. More importantly, these long-term (daily for up to 9 months) exposure schedules were found to be very safe because they did not demonstrate any harmful effects including, no effects on brain oxidative stress or abnormal brain histology, no significant brain heating, no damage to DNA in circulating blood cells, and no gross changes to peripheral tissues. Another study performed at a higher frequency (1950 MHz, SAR 5 W/kg, 2 h/day, 5 days/week) was also found to ameliorate AD pathology in Tg-5xFAD and wild type (WT) mice exposed to REMFS for 8 months [38]. Remarkably, long-term REMFS significantly decreased not only Aβ plaques, APP, and APP carboxyl-terminal fragments in whole brain (including hippocampus and entorhinal cortex), but also inhibited the parenchymal expression of beta-amyloid precursor protein cleaving enzyme 1 (BACE1) and neuro-inflammation. Additionally, REMFS recovered memory impairment in AD mice. Furthermore, treated Tg showed expression of 5 genes (Tshz2, Gm12695, St 3 gal1, Isx and Tll1), which are associated with Aβ metabolism. We found that these genes are significantly altered inTg-5xFAD mice, showing diverse responses to the treatments in the hippocampus of wild control and transgenic mice. Treatment in wild type mice showed no difference than control Tg. Conversely, REMFS-treated Tg group showed contrasting gene expression arrays. All these findings suggest REMFS treatments positively alter Aβ deposition and metabolism in AD, but not in wild type mice [38].
Together, human neurons and AD model mouse experiments suggest that REMFS exposures decrease Aβ at the extra and intra cellular levels. Different from the clinical trials with active and passive immunization, REMFS did not cause encephalitis or inflammation. REMFS has important effects in preventing and decreasing brain Aβ deposition, therefore making REMFS a potential therapeutic strategy in the treatment of advanced AD patients who have massive Aβ aggregation in the brain.
Considering the REMFS effects in Tg AD mice, the results on primary neuronal cultures are very promising as the REMFS parameters such as frequency and SAR we applied creates an appropriate and safe potential new therapeutic strategy for human exposures. However, before we exposed humans to this type of RF radiation, we need to recognize that extrapolating effects of mice exposure to effects of human exposure is complex. The mouse’s geometry, size, tissue penetration, tissue dielectric properties are significantly different from that of a human and therefore the external fields produced during the 915 MHz exposure would result in quite different internal fields. Internal fields are the electromagnetic fields inside the object, and not the electromagnetic fields incident upon the object. The energy absorbed by an object is directly related to its internal field. Consequently, it is imperative to determine what type of external fields could yield the same internal fields in mouse and human. An important EMF parameter to contemplate is tissue penetration; we should consider that tissue penetration is inversely proportional to the EMF frequency. For example, 918 MHz (frequency used in mouse experiments and cell phone) has a skin penetration of less than 4 cm in a human head, while it is a whole-body exposure for a mouse. Human head thickness for an adult male is around 19.4 cm, so to irradiate the center of a human head the exposure should have a skin penetration of minimum of 9.7 cm. This demonstrates that the 918 MHz frequency is not able to reach important deep brain areas such as the hippocampus. Additionally, 918 MHz produced a greater energy than REMFS, so rising the thermal injury risk. Instead, REMFS exposure (64 MHz) has a skin penetration of 13.49 cm, similar to the 14.5 width of a human head making it suitable for a human head.
Using similarities in dosimetry between cell cultures, animal exposure, human phantom exposure, and computer simulation it is possible to adjust conditions for human exposure [70]. Thus, we used frequencies more suitable for human exposures (50–75 MHz). The basis for these frequencies was:
MRI machines has been used 64 MHz for several decades giving a safe exposure that is similar to the 50 and 64 MHz used in our previous experiments [39].
It is similar to the human whole body resonant frequency (75 MHz), [71] at this frequency the body absorbs up to 10 times as much as power as when it is not in resonance [72]. Consequently, we would need to apply less power and achieve the minimum SAR that could achieve biological effect, a safer exposure compared to high energy fields. This would decrease the complexity of the EMF-biological system interaction decreasing the heat production from the exposure.
The physical and biological conditions of the exposed target would affect the EMF parameters of the exposures concerning the case under study [73].
Our REMFS exposures produced a SAR (0.4–0.9 W/kg) well below the value limits values of 2 W/kg set by the Institute of Electrical and Electronics Engineers (IEEE) [40], so offering a safe framework for clinical trials [39]. The REMFS parameter for human exposures will range from daily to twice weekly, with a length extending from 30 min to 1 h for several months founded on human neurons and AD mouse studies [36, 37, 39, 40, 41].
In our previous studies, we determined that REMFS enhanced the HSF1-DNA and delayed the aging process. Taking into consideration that the decline in proteostasis is the earliest event in the aging process and that it is caused by attenuation of the HSF1-DNA binding [66, 74], this makes REMFS a potential therapeutic strategy to treat age-related diseases.
Nevertheless, we should take into consideration other pathway imbalances that cause the pathomolecular mechanism of age-related diseases. Take, for example, the Forehead box protein (FoxO) pathways whose dysregulation results in accelerating the aging process [75]. This suggests that delaying the aging process may be achieved by reactivation of both HSF1 and FoxO pathways (longevity pathways). The combination of the treatments for these two pathways such as HSF1 enhancers (REMFS) in combination with caloric restriction mimetics such as resveratrol (RV) would be an appropriate therapeutic strategy [69, 76]. Enhancing these two pathways that control an array of different processes, including metabolism, cognition, stress response, and brain plasticity demands close monitoring to prevent hyperstimulation of either pathway, thus controlling side effects [69]. For this reason, we suggest using REMFS because 64 MHz affords a safe framework for human treatments [77]. Our previous studies utilized a non-ionizing EMF radiation of 50 MHz allowed safe exposures comparable to our recent study in human neurons with 64 MHz [39]. We should take into consideration that 918 MHz has less skin penetration and therefore the energy carried by the exposure is absorbed adjacent to the skin. In an interest study the RF exposure during 30 min with a 2.7–4 W/kg SAR, versus a 16 min with 6 W/kg both caused a noteworthy temperature change (0.1–0.4°C), as well as other physiological changes in heart rate, localized sweating, and blood flow [78], thus, we suggest lower and effective SAR values (0.4–0.9 W/kg) to prevent these side effects. REMFS can be applied through different exposure systems such as antennas in anechoic chambers or large TEM chambers, these chambers would likely about 10 m in length, 6 m in height, and 6 m in width and utilized frequencies between 50 and 64 MHz [79, 80]. The Institute of Electrical and Electronics Engineers (IEEE) recommend maximum permissible exposure (MPE) values of less than 1 W/kg [81]. Our REMFS treatment produce SAR’s under this limit, so suggesting that this is a safe exposure for human treatments. An important aspect to consider is the homocysteinylation of the HSF1 which could be the cause of the age-related attenuation of the HSF1-DNA binding. Therefore, decreasing plasma homocysteine levels by dietary interventions is recommended to prevent the HSF1-DNA binding [82].
Likewise, FoxO activation is a very crucial part of the combination therapy to delay the aging process and age-related diseases. RV is one of the most effective FoxO activators; it has few side effects and it is easy to administer. RV also activates the mTOR, and SK1N pathways [83]. RV has effects on multiple pathways such as antioxidant, vasodilating, inflammation, cell growth, atherosclerosis, anticoagulant, and beneficial for the cardiac rhythm. Notably, RV decreases mortality and metabolic syndrome in high-calorie and high-fat diets in mice experiments [84]. For these reasons RV is a potentially a new therapeutic strategy to prevent and treat metabolic syndrome and diabetes mellitus type II. One disadvantage is that RV bioavailability is poor as a consequence of metabolic alterations in the plasma. Hypothetically, REMFS combines with RV as soon as a decline in any of these two pathways is detected. One of the methods to determine if the HSF1 pathway is failing would be monitoring the T lymphocyte HSF-1 DNA binding [69]. The method to detect a decline in the FoxO pathway includes testing the FoxO3a binding to DNA. An important part of the evaluation is to determine the aggregation of beta amyloid (Aβ), Tau, or α-synuclein proteins in the human brain using Positron-emission tomography (PET) scanning to monitor neuro-degeneration and protein deposition load [69, 85].
While REMFS might affect the organism in a whole-body basis, we also consider that more focused exposures, individual body targets may be selected. Any organ that shows functional decline, including the brain, kidneys, joints, liver, or heart, may benefit from engineered REMFS to induce protein disaggregation by activation of the HSF1 pathway. Therefore, we will initiate human head exposure to treat the most common cause of dementia (Alzheimer’s disease). Before clinical trials are considered we have to determine the best electromagnetic settings for human exposures such as power output, power deposition, far field, antenna type, distance from antenna, electric field, magnetic field, etc. that will produce uniform internal fields similar to our previous studies when applied to a human brain with a target SAR of 0.4–0.9 W/kg [40]. Initially, we determined by mathematical and computer modeling that the REMFS exposures in our biological studies delivered a safe thermal and SAR measurements [70]. With these results we developed a virtual exposure system by numerical model and computer simulation. We designed a virtual antenna that delivers a SAR of around 0.6 W/kg to a simulated phantom of a human brain. With these simulations we found the REMFS parameters that would deliver a uniform radiation to a human skull in clinical trials [86]. In the near future, we will experimentally confirm these results using an appropriate antenna to expose a Specific Anthropomorphic Mannequin (SAM) human head phantom [87] with internal and external probes oriented vertically to determine the EMF parameters that will provide an effective and safe SAR for future Alzheimer’s treatment. Data suggest that the ideal environment for these treatments should be an anechoic chamber to prevent RF wave reflections and provide a uniform exposure to the subjects. The final step will be to initiate phase 1 clinical trials in patient with early Alzheimer’s disease to determine safety and efficacy of this new potential therapeutic strategy.
We performed several computer modeling and simulation to create visual representations of the interior of the human body for diagnostic analysis, as well as visual representation of the function of some organs or tissues. We utilized EMF of different frequencies up to 5 GHz because they are commonly used in medicine for diagnosis. Here, we show several future non-invasive EMF diagnostic procedures.
We performed microwave and thermal simulation of human bone. The results showed differential power dissipation over the bone materials with different temperatures within 2–4° change for various frequencies [88]. This simulation also showed the distinction between normal and abnormal bone tissues, indicating that this is an effective method for diagnosing normal bone and pathological bone including bone cancer, fractures and infection.
We also performed simulations of the vasculature of the femoral bone [89]. Disruption of the blood supply to the femoral neck is a well-recognized source of morbidity and mortality, often resulting in avascular necrosis of the femoral head. EM simulations of femoral neck fractures were presented as examples. Electric fields were generated in a fashion that exploited disruptions within the vasculature of the femoral neck. Simulated blood vessels were developed in two-dimensions: the phi direction (the circular), and the z-direction. Two different frequencies, 3 and 5 GHz were considered, with 100-J energy pulses within blood vessels of 2.54 mm in diameter. The fat surrounding the bone was simulated, we also developed an additional model with layered fat and skin above the vessels. We were able to visualize the femoral neck’s blood vessels. This research validated the technique of detecting and diagnosing pathology of the circulation of femur bone in humans. The approach using the characteristics of the RF response of the reflected power at various frequencies as determined from the finite element simulation was appropriate, and it fits well with the practical model if implemented via MEMS (micro-electro-mechanical systems). Magnetic sensors may be built on flexible substrates in order to shape up the sensors and make them suitable for measuring various sizes. The COMSOL models were made close to the anatomical model seen in Figure 2. It shows the head, neck, and leg of the femur. The exploitation of electric field indicates the feasibility of a subsequent practical model to diagnose femur vasculature pathology including avascular necrosis of the femoral neck and other human bones.
(a) The computerized model of the femur (b) The anatomical femur with components and blood vessels: blood vessels showing rupture in the femur vasculature.
We lastly performed simulations to detect arteriosclerosis of human blood vessels which is associated with coronary artery and peripheral vascular disease. Our laboratory developed a new non-invasive EMF approach for the diagnosis of stenosis/arteriosclerosis disease. A simulated human foot was analyzed using COMSOL multi-physics software in attempt to visualize, analyze, and quantify the degree of peripheral vascular disease, which plays a pivotal role in the development of diabetic foot ulcers. The simulation results served as a proof of concept for predicting and stratifying certain degrees of occlusion within the peripheral vasculature. Although this study was based on computer modeling with simulation results in nature, the research parameters shows promise for practical models for future diagnosis of the peripheral vasculature via EM parameters. The study shows promises for the practical implementation of the device. Current technologies with MEMS/NEMS can serve as hardware systems proper for this diagnosis process designed for detecting EM parameters needed for the diagnostic tool for the early detection of peripheral vascular disease, and ultimately, diabetic foot ulcers [90].
Since the discovery of electromagnetic fields, the beneficial health effects and their potential applications toward the treatment and diagnostic of age-related diseases has been eagerly sought with promising results. The effect of non-thermal, non-ionizing REMFS has been examined in our laboratory for its ability to induce cytoprotecting effect via the heat shock factor-1. Results suggest anti-aging effects occurred as a direct consequence of a biological systems-REMFS interaction, and herein we have proposed a quantum tunneling-based mechanism mediated by the interfacial water to explain it. Our pioneering studies have also demonstrated safe REMFS decreases toxic Aβ levels in primary human brain cell cultures; an outcome likely resulting from increased Aβ degradation. When considered in parallel with several transgenic AD mouse model studies that have demonstrated the efficacy and safety of REMFS in-vivo to induce removal/disaggregation of pre-existing Aβ deposits and prevent or reverse cognitive impairment, the potential application of REMFS toward the treatment of AD and age-related protein deposition diseases is certainly encouraging. Furthermore, the simultaneous modulation of longevity pathways through HSF1 enhancers (e.g., REMFS) and FoxO pathway up-regulators (caloric restriction mimetics, such as resveratrol) suggest complementary strategies could act synergistically to balance and preserve cellular defense and repair systems. As REMFS targets the most important pathways affected in Alzheimer’s disease and other age-related pathologies, HSF1 modulation and enhancement by REMFS could potentially restore a variety of damaged signaling networks associated with the aging process, additionally, diagnostic EMF devices could prove to be a fast, non-invasive, and painless tool that will avoid incisions into the body and the removal of tissue for diagnosis of a multitude of diseases.
EMF | electromagnetic fields |
REMFS | repeated electromagnetic fields stimulation |
SAR | specific absorption rate |
HSF1 | heat shock factor 1 |
HB | hydrogen bond |
FLIFW | first layer of the interfacial water |
GRNA | guanine of the RNA |
O | oxygen |
HSP | heat shock proteins |
HSR1 | heat shock RNA |
RV | resveratrol |
FoxO | Forkhead box protein |
Aβ | amyloid beta |
AD | Alzheimer’s disease |
SOD | superoxide dismutase |
WT | wild type |
Tg | transgenic |
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\\n\\nOur reputation – Everything we publish goes through a two-stage peer review process. We’re proud to count Nobel laureates among our esteemed authors. We meet European Commission standards for funding, and the research we’ve published has been funded by the Bill and Melinda Gates Foundation and the Wellcome Trust, among others. IntechOpen is a member of all relevant trade associations (including the STM Association and the Association of Learned and Professional Society Publishers) and has a selection of books indexed in Web of Science's Book Citation Index.
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\\n\\nOur reach – Our books have more than 130 million downloads and more than 146,150 Web of Science citations. We increase citations via indexing in all the major databases, including the Book Citation Index at Web of Science and Google Scholar.
\\n\\nOur services – The support we offer our authors and editors is second to none. Each book in our program receives the following:
\\n\\nOur end-to-end publishing service frees our authors and editors to focus on what matters: research. We empower them to shape their fields and connect with the global scientific community.
\\n\\n"In developing countries until now, advancement in science has been very limited, because insufficient economic resources are dedicated to science and education. These limitations are more marked when the scientists are women. In order to develop science in the poorest countries and decrease the gender gap that exists in scientific fields, Open Access networks like IntechOpen are essential. Free access to scientific research could contribute to ameliorating difficult life conditions and breaking down barriers." Marquidia Pacheco, National Institute for Nuclear Research (ININ), Mexico
\\n\\nInterested? Contact Ana Pantar (book.idea@intechopen.com) for more information.
\\n"}]'},components:[{type:"htmlEditorComponent",content:'We have more than a decade of experience in Open Access publishing. The advantages of publishing with IntechOpen include:
\n\nOur platform – IntechOpen is the world’s leading publisher of OA books, built by scientists, for scientists.
\n\nOur reputation – Everything we publish goes through a two-stage peer review process. We’re proud to count Nobel laureates among our esteemed authors. We meet European Commission standards for funding, and the research we’ve published has been funded by the Bill and Melinda Gates Foundation and the Wellcome Trust, among others. IntechOpen is a member of all relevant trade associations (including the STM Association and the Association of Learned and Professional Society Publishers) and has a selection of books indexed in Web of Science's Book Citation Index.
\n\nOur expertise – We’ve published more than 4,500 books by more than 118,000 authors and editors.
\n\nOur reach – Our books have more than 130 million downloads and more than 146,150 Web of Science citations. We increase citations via indexing in all the major databases, including the Book Citation Index at Web of Science and Google Scholar.
\n\nOur services – The support we offer our authors and editors is second to none. Each book in our program receives the following:
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\n\nInterested? Contact Ana Pantar (book.idea@intechopen.com) for more information.
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