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Single Gene Inactivation with Implications to Diabetes and Multiple Organ Dysfunction Syndrome


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Nutritional and environmental epigenetics are involved with the repression of anti-aging genes that are linked to the chronic disease epidemic. Unhealthy diets inactivate the calorie sensitive gene Sirtuin 1 (Sirt 1) involved in epigenetic processes that promote immune system alterations, mitochondrial apoptosis, Non-alcoholic Fatty Liver Disease (NAFLD), diabetes and Nitric Oxide (NO) modification with relevance to core body temperature involved with appetite regulation, glucose homeostasis and hepatic xenobiotic metabolism. The interplay between NO and epigenetics has attracted interest with relevance to autoimmune disease and mitophagy that has become of critical concern to diabetes and the development of MODS. Future research involved with nutritional research and the maintenance of Sirt 1 transcriptional control is critical to the prevention of MODS that is linked to the immune system and insulin resistance. In the developing world bacterial lipopolysaccharides a critical repressor of Sirt 1 is now involved with NAFLD and various organ diseases relevant to tissue accumulation of xenobiotics from various environments with relevance to MODS and the global chronic disease epidemic.
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Research Article
Vol. 3 No. 3: 24
DOI: 10.21767/2472-1158.100058
© Under License of Creative Commons Attribution 3.0 License | This article is available in: hp://www.clinical-epigene
Journal of Clinical Epigenetics
ISSN 2472-1158
Ian James Martins1-3*
1 Centre of Excellence in Alzheimer’s
Disease Research and Care, School of
Medical and Health Sciences, Edith
Cowan University, Australia
2 School of Psychiatry and Clinical
Neurosciences, The University of
Western Australia, Nedlands, 6009,
3 McCusker Alzheimer's Research
Foundaon, Hollywood Medical
Centre, Nedlands, 6009, Australia
*Corresponding author: Ian Marns
Centre of Excellence in Alzheimer’s Disease
Research and Care, School of Medical and
Health Sciences, Edith Cowan University,
270 Joondalup Drive, Joondalup, Western
Australia 6027, Australia.
Tel: +61863042574
Citaon: Marns IJ (2017) Single Gene
Inacvaon with Implicaons to Diabetes
and Mulple Organ Dysfuncon Syndrome. J
Clin Epigenet. Vol. 3 No. 3:24
Specic genes that are involved in epigenecs are sensive to
nutrional regulaon, oxidave stress and the development
of insulin resistance that can result from changes in cellular
chroman structure, DNA methylaon and histone modicaons
with relevance to the global chronic disease epidemic [1-7].
Epigenec modifications in specific cells such as the brain,
adipose tissue and liver are more sensitive than other tissues
[4]. Epigenetic modifications induced by unhealthy diets or
environmental xenobiotics involve the anti-aging genes [8]
that alter gene expression in the Suprachiasmatic Nucleus
(SCN) in the brain [4,5] with effects on peripheral lipid
metabolism and energy expenditure that involve the adipose
tissue and liver with immune alterations [9-11] that determine
the survival of cells in various tissues (Figure 1).
In the developing world with urbanizaon and increased access
to food epigenec and immune system alteraons are associated
with increased chronic disease suscepbility. Down regulaon
of an-aging genes reduces hepac xenobioc (soil, air, water)
metabolism and may promote mulple organ dysfuncon
Received: July 20, 2017; Accepted: July 27, 2017; Published: August 01, 2017
Single Gene Inacvaon with
Implicaons to Diabetes and Mulple
Organ Dysfuncon Syndrome
Nutrional and environmental epigenecs are involved with the repression of
an-aging genes that are linked to the chronic disease epidemic. Unhealthy diets
inacvate the calorie sensive gene Sirtuin 1 (Sirt 1) involved in epigenec processes
that promote immune system alteraons, mitochondrial apoptosis, Non-alcoholic
Fay Liver Disease (NAFLD), diabetes and Nitric Oxide (NO) modicaon with
relevance to core body temperature involved with appete regulaon, glucose
homeostasis and hepac xenobioc metabolism. The interplay between NO and
epigenecs has aracted interest with relevance to autoimmune disease and
mitophagy that has become of crical concern to diabetes and the development
of MODS. Future research involved with nutrional research and the maintenance
of Sirt 1 transcriponal control is crical to the prevenon of MODS that is linked
to the immune system and insulin resistance. In the developing world bacterial
lipopolysaccharides a crical repressor of Sirt 1 is now involved with NAFLD and
various organ diseases relevant to ssue accumulaon of xenobiocs from various
environments with relevance to MODS and the global chronic disease epidemic.
Keywords: Diet; Sirtuin 1; Suprachiasmac nucleus; Circadian; Xenobioc
syndrome (MODS) [12-14]. These toxic compounds are involved
in nuclear receptor dysfuncon such as the nuclear receptor
Sirtuin 1 (Sirt 1) [5] that determines the survival of man and
various species with relevance to toxicity to mitochondria in
neurons [15,16] and cells in peripheral ssues [17-27].
Sirt 1 Repression with Accelerated Brain
Aging and Organ Disease
The defecve gene in various chronic diseases [28-38] is Sirt 1
a NAD(+)dependent class III histone deacetylase (HDAC) protein
that targets transcripon factors to adapt gene expression to
metabolic acvity, insulin resistance and inammaon. Interests
in Sirt 1 have increased since it may override the eects of other
an-aging genes such as Klotho, p66Shc (longevity protein) and
Fork head box proteins (FOXO1/FOXO3a) [8]. In adipose ssue
gene expression proles of Klotho, p66Shc (longevity protein)
2This article is available in: hp://www.clinical-epigene
Vol. 3 No. 3: 24
Journal of Clinical Epigenetics
ISSN 2472-1158
and Fork head box proteins (FOXO1/FOXO3a) have been
completed and indicate down regulaon of these genes are
related to mitochondrial apoptosis, adipogenesis and adipocyte
dierenaon [29-38]. Sirt 1 is central to the down regulaon
of the other an-aging genes via its role as a deacetylase of the
transcripon factor p53 [8]. Sirt 1/p53 dysregulaon is important
to mitochondrial apoptosis [4] and p53 interference has become
a key defect in biology [39-42] with relevance to MODS and the
diabetes epidemic.
The main types of brain cells are the glial cells (astrocytes,
oligodendrocytes, and microglia) and the interacon of the glial
cell referred to as the astrocyte with the neuron are essenal to
maintain neuron life span and prevent neurodegenerave disease
[43]. Neurons in the brain with Sirt 1 repression may undergo
early programmed cell death [44] with altered astrocyte neuron
interacons that lead to accelerated brain aging [45]. Sirt 1 and
its dysfuncon in the brain involves the SCN and Sirt 1 repression
inacvates the SCN that is involved with appete regulaon,
body glucose control, circadian rhythm and hepac xenobioc
metabolism [5,46]. Xenobiocs interfere with Sirt 1’ regulaon
of DNA repair [47,48] and p53 transcriponal regulaon [39-42]
with relevance to interference with mitochondrial biogenesis
[4,49,50] and promoon of mitochondrial apoptosis in neurons
with eects on synapc plascity [51-58].
Sirt 1 acvaon of the non amyloidogenic α-secretase is involved
in the processing of the amyloid precursor protein (APP) to reduce
amyloid beta generaon [59]. Sirt 1 dysregulaon increased
toxic amyloid beta formaon associated with mitochondrial
apoptosis [60]. SCN and its regulaon of core body temperature
[61] has become of major interest to species survival with Sirt 1
now regarded as the heat shock gene [62-64] with temperature
regulaon crical to Sirt 1 regulaon of insulin resistance and
xenobioc metabolism [5,65,66]. Sirt 1 involvement in telomere
maintenance maintains chromosome stability and its regulaon
of telomere length may be nullied by increased xenobiocs with
telomere length shortening [4,5,67,68].
Sirt 1 eects on p53 gene regulaon supersede micro RNA
(miRNAs) regulaon of p53 [69-71] with relevance to their role
in various chronic diseases [17-27]. MiRNAs such as miR-34a [72]
and miR-122, miR-132 [73,74] inhibit Sirt 1 and may inacvate
p53-miRNA interacons. Interference with cellular miRNA
by diet, drugs and xenobiocs are now relevant to Sirt 1/p53
dysregulaon and cell apoptosis. MiRNAs may regulate Sirt 1/p53
regulaon of nuclear receptors such as peroxisome proliferator-
acvated receptor-gamma co-acvator (PGC-1 alpha) and
Pregnane X Receptor (PXR) with interference with xenobioc
metabolism relevant to mitochondrial biogenesis [4,5,75,76].
Other nuclear receptors such as peroxisome proliferator-
acvated receptor gamma (PPAR gamma), PPAR alpha, beta/
delta, liver X receptors (LXR)/liver receptor homolog-1 (LRH-1)
involved in energy, glucose, cholesterol, fay acid metabolism
are regulated by Sirt 1 with connecons between hepac nutrient
and xenobioc metabolism (PXR, CAR and xenobioc sensing
nuclear receptor) involved in the expression of cytochrome p
450 (CYP 450) enzymes [5]. Increased levels of xenobiocs in
the plasma and various ssues may lead to increased reacve
oxygen species associated with low Sirt1 acvity [77,78] which is
associated with chronic diseases in developing countries.
SCN dysfuncon in diabetes with
relevance to MODS
Insulin resistance and beta cell dysfuncon has been associated
with the development of MODS [79,80]. In Type 2 diabetes more
than 150 genec loci are associated with the development of
diabetes and 50 candidate genes have shown to play a major
part in the development of the disease [81]. These genes are
involved in pancreac β cell funcon, insulin acon and glucose
metabolism in metabolic condions. In Type 1 diabetes the HLA
class genes have been associated with Type 1 diabetes with
dierences in haplotypes in ethnic groups such as Caucasians,
African, Americans, Japanese and Chinese [46]. Sirt 1 regulaon
of the MODY gene via transcripon factors hepatocyte nuclear
factor 1 has been shown with evidence of genec regulaon
of liver and pancreas in Type 1 diabetes [81]. Nutrional
dysregulaon of Sirt1 and the SCN may now involve Type 1,
Type 2 and Type 3 diabetes (Figure 2) [63,82] and induce MODS
that involves accelerated organ diseases with hepac xenobioc
metabolism (NAFLD) completely inhibited in these individuals.
Sirt 1 repression induces mitophagy with the development of
MODS and may supersede the connecons between diabec
genes (Type 1 and 2) and their associated diseases (Figure 2). Sirt
1 plays an important role in the regulaon broblast growth factor
21 [82-84] and the apelinergic pathway [85] with connecons
to brain insulin resistance (stroke, demena, AD) [86]. In Type
2 diabetes the relevance of stress, anxiety and hyperphagia are
associated with defecve apelinergic pathways [85] and severity
of diabetes (post-transcriponal defect) associated with Sirt
1-apelinergic system defects in mental disorders [87].
Dysregulated Sirt 1 on adipocyte dierenaon and senescence
involves gene expression and secreon of adiponecn with eects
Figure 1 Nutrional diets and environmental xenobiocs
are now involved with the repression of an-aging
genes with epigenec alteraons linked to the global
chronic disease epidemic. Circadian dyssynchrony and
immune system imbalances involve mitochondrial
apoptosis in many ssues with relevance to diabetes
and Mulple Organ Disease Syndrome (MODS).
© Under License of Creative Commons Attribution 3.0 License
Vol. 3 No. 3: 24
Journal of Clinical Epigenetics
ISSN 2472-1158
on the release of adipokines and cytokines that are implicated
in NAFLD and chronic diseases [88-97]. Sirt 1 interacons with
forkhead transcripon factor O1 (FOXO1), C/EBP alpha may
involve Klotho C/EBP alpha and peroxisome Proliferator-Acvated
Receptor (PPAR) interacons [98-103] important to mitochondrial
funcon and adipocyte dierenaon. Furthermore miR-122
and miR-132 [4] have been shown directly inhibit Sirt 1 and may
interfere with adipose ssue adiponecn release. FGF21 binds
to FGF receptor and beta koltho receptor complex [104-108]
and acvates adipose ssue Sirt 1/p53 with interacons with
relevance to PGC1-alpha, peroxisome proliferator acvated
receptor gamma, FOXO 1 [109-111] and AMP acvated protein
kinase (AMPK) involved in adipocyte ssue transformaon.
FGF21 and Sirt 1 are essenal for liver mitochondrial funcon
(Figure 2) and regulate pancreas mitochondrial biogenesis and
beta cell insulin secreon [112].
Sirt 1 eects on hepac cholesterol metabolism and NAFLD are
mediated via Sirt 1 and transcripon factor C/EBP alpha that
regulates the transcripon of the apolipoprotein B gene [113].
The protein kinase c-jun amino-terminal kinase 1 (JNK1) can
phosphorylate Sirt 1 with phosphorylaon of Sirt 1 important
to p53 acvaon with relevance to NAFLD and the metabolic
syndrome [46]. Sirt 1 and its connecons to NAFLD may
involve Brd4/p53 interacons with relevance to Brd 4-P-TEFb
involvement in mitoc progression [46,114]. The control of
the adipose ssue-liver crosstalk (gene expression) by the SCN
is defecve in diabetes (Type 3) and related to excess calorie
consumpon or core body temperature that overrides the Sirt
1 related SCN entrainment [61]. SCN defects are related to the
peripheral circadian clock dyssynchrony [115] (adipose ssue-
liver cross talk) that determine Sirt 1 regulaon of low adiponecn
and melatonin levels involved in the metabolic syndrome, NAFLD
and reverse cholesterol transport [61,83,116] with relevance to
diabetes and the severity of MODS (Figure 2).
Epigenec Modicaons Involve Nitric
Oxide and Immune Dysregulaon in
Inducon of epigenec alteraons that determine brain
dysfuncon involve Nitric Oxide (NO) homeostasis and eect the
adipose ssue-liver crosstalk with relevance to immune alteraons
that determine the survival of cells in various ssues. Diabec
individuals with defecve SCN and brain-liver crosstalk involve
immune imbalances as the primary cause of MODS. In Type 3/
Type 2 individual’s reduced xenobioc metabolism is associated
with NAFLD and the inducon of MODS connected to the immune
system. Sirt 1/p53 transcriponal responses are involved in NO
metabolism [85,117-119] and immunometabolism regulated by
diet, drugs and the environment are crical to mitochondrial
apoptosis and the inducon of NAFLD in the developed world.
Sirt 1 is connected to immunometabolism [9] and adipogenesis
disorders with adipose ssue release of adipokines, inammatory
cytokines, heat shock proteins and natural killer cells relevant to
mitophagy in diabetes and MODS. Sirt 1 is essenal to maintain
the SCN, NO homeostasis [85] and its dysfuncon is crical to
the defecve circadian rhythm of heat shock proteins [60-63]
with relaon to cellular immune response [9,120]. Sirt 1 and
its regulaon of autoimmune disease is central to defecve
liver fat metabolism [9] with maintenance of Sirt 1 in adipose
ssue and the liver of crical importance to MODS. Heat/cold
stress inacvate the heat shock gene Sirt 1 [60-63] with NO
dyshomeostasis, immune system imbalances connected to
mitophagy (Figure 3) [4,5,9]. NO regulaon of p53 [117-119] is
important to epigenec regulaon and Sirt 1 post-transcriponal
regulaon by NO [85,121-123] involves p53/miRNA [4,124,125],
an-aging gene p66shc [126-128], klotho [129-131], FOXO 3a
[132,133], transcripon factors PGC1 alpha [132,134,135], PPAR
[136-138], LXR-ABCA1 [139,140], AMPK signalling [85,141,142],
HSP/body temperature regulaon [143-146] and glucose
homeostasis [147,148]. The importance of Sirt 1 and the immune
response is now consistent with its interplay between NO and
epigenecs [149,150] with relevance to human health and
disease (Figure 3). The role of NO and cytochrome p450 complex
formaon [151-153] has become relevant to cytochrome P450
expression in xenobioc metabolism [5] with increased liver
NO [85] implicated in the inacvaon of Sirt1/PXR’s control of
xenobioc metabolism [4,5,154,155]. Sirt 1 and its regulaon of
immunometabolism [9] are connected to xenobioc metabolism
with implicaons to MODS and xenobioc induced immune
alteraons [156,157]. Xenobiocs may nullify Sirt 1’s role in NO
homeostasis and vasodilaon in the heart [85] with relevance
to interference of therapeuc drugs for blood vessel dilaon
[158]. NO regulates calcium signalling in various cells [159-161]
and in the SCN alteraons in cell calcium is crical to circadian
dyssynchrony [162].
Lifestyle factors with Nutrional intervenons may reverse Global
chronic disease Low calorie diets that upregulate Sirt 1 promote
an-aging gene therapy, miRNA funcon, transcriponal factor
Figure 2 Nutrional regulaon of Sirt 1 is important to
prevent insulin resistance and mitophagy in diabec
individuals. Individuals with Type 3/Type 2 diabetes
have SCN defects with accelerated NAFLD and MODS
associated with hepac xenobioc metabolism and
4This article is available in: hp://www.clinical-epigene
Vol. 3 No. 3: 24
Journal of Clinical Epigenetics
ISSN 2472-1158
p53/miRNA, Anti-aging genes (p66she, klotho, FOXO 3a)
LXR-ABCA1), Signalling JNK1 or AMPK pathway
Transcription factors, Nuclear receptors (PGCI alpha, PPAR,
Figure 3 The heat shock gene Sirt 1 is crical to NO
homeostasis, immune system imbalances connected
to mitophagy. NO, nuclear receptor signalling and the
immune response is now connected to MODS. The
role of NO and cytochrome p450 complex formaon
has become relevant to inacvaon of Sirt 1 post-
transcriponal regulaon of PXR/cytochrome P450
expression essenal to maintain hepac xenobioc
control and interacve nuclear receptor signalling in various cells
and ssue with relevance to maintenance of immune response
and prevenon of autoimmune disease that may be connected
to global chronic disease and the development of MODS (Figure
3). Bacterial LPS is involved with NAFLD and interference with
hepac xenobioc metabolism is relevant to increased mitophagy
and neurodegeneraon. Nutrional diets with Sirt 1 acvators
[162] have become important to molecular and genec medicine
with relevance to immune disturbances and mitophagy [9,60]
in diabetes and MODS (Figure 3). Anxiety, stress and heat/cold
stress may induce heat shock protein-mitophagy [9,60,61,63]
relevant to brain disease. Sirt 1 inhibitors [162,163] may interfere
with dietary regulaon of immune responses and accelerated
autoimmune disease relevant to chronic disease and MODS.
Global chronic diseases involve cellular immune alteraons
that lead to mitophagy in various ssues. High calorie diets are
involved with transcriponal dysregulaon and defecve hepac
xenobioc associated with immunometabolism disorders in
genec medicine. Nutrional regulaon of Sirt 1 is essenal
to maintain the interplay between NO, glucose homeostasis,
immune system and various nuclear receptors, transcripon
factors/signalling factors and miRNA involved in epigenecs
with relevance to human diabetes. Bacterial LPS induced Sirt
1 repression in Type 3/Type 2 diabetes induce NAFLD with
increased xenobioc levels linked to the development of MODS
and global chronic disease in the developing world.
This work was supported by grants from Edith Cowan University,
the McCusker Alzheimer's Research Foundaon and the Naonal
Health and Medical Research Council.
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... Sirtiun 1 (Sirt 1) gene regulates food intake which controls life span and several chronic diseases including obesity and cardiovascular disease with effects on NAFLD, cognition, energy metabolism, inflammation, mitochondrial biogenesis, neurogenesis, glucose/cholesterol metabolism and amyloidosis. It is a class III nicotinamide adenine dinucleotide, which is a (NAD+) dependent histone deacetylase (HDAC) [123,124]. He plays the following important other roles: ...
... Caffeine is essential for the avoidance of blood brain barrier disruption but with NAFLD, excessive transport of caffeine to the brain is connected with neurodegeneration. Coffee may contain ochratoxin A which is a powerful neurotoxin applicable to mitochondrial apoptosis and which supersedes Sirt's regulation of mitochondrial biogenesis related to neurodegeneration [123][124][125]. ...
... Sirt is very importance because it can cancel the effects of other antiaging genes such as Klotho, p66Shc (longevity protein) and Fork head box proteins (FOXO1/FOXO3a). In Klotho adipose tissue gene expression profiles, p66Shc (longevity protein) of telomere length may be canceled by increased xenobiotics with shortening of telomere length [123][124][125]. ...
... The Sirtuin 1 activators have been used for diabetes treatment and the 19 antidiabetic plants presented above need to be assessed for this anti-aging gene activation. So the insulin resistance and organ suicide are closely connected [64]. Food intake or unhealthy diets is regulated by Sirtuin 1, which is essential to maintain the interaction between glucose homeostasis, immune system and numerous nuclear receptors, transcription factors/signaling factors and miRNA intricate in epigenetics with relevance to human diabetes [65]. ...
... Prevention of insulin resistance has appeared as the primary prevention program in populations worldwide with enhanced zinc intake and maintenance of nitric oxide homeostasis in cells essential to avoid early modifications several anti-aging genes, neuropeptides and endocrine hormones connected with the regulation of appetite, insulin resistance and cellular apoptosis. Anti-aging therapy comprises low-calorie diets that do not contain LPS, mycotoxins or xenobiotics and these diets maintain Sirtuin 1 activity of the brain and liver with appetite regulation thoroughly associated to zinc homeostasis and nitric oxide related to the autonomic control of the liver by the brain [64][65][66][67]. ...
... These enhancement effects may lead to hypoglycemia, meaning there is a high likelihood of adverse events. In addition, an increasing number of studies showed that genetic variations may involve the pharmacokinetic or pharmacodynamic pathways to affect HDIs; hence, monitoring is necessary [44,45]. ...
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Background: It is well known that diabetic patients use Herbal Medicines (HMs) and antidiabetic drugs concurrently. Therefore, there is always the possibility of Herb-Drug Interactions (HDIs). This study attempted to find an appropriate path to accurately assess the risk of HM usage by diabetic patients. Methods: The natural medicines comprehensive database and other resources were used to assess the risk of HDIs for about 130 herb-drug combinations used by 38 patients. Result: Most of these interactions were assessed as “moderate interactions”, with only one assessed as a “major interaction”. No adverse events or harm were reported as the assessments were carried out retrospectively. The vast majority of the evidence on HDIs was based upon the pharmacological activities of the herbal and conventional medicines rather than the clinical outcomes. Conclusion: Our assessments highlight the gulf between theoretical and real clinical interactions. Although this type of assessment does not measure the actual harms/benefits of HDIs, it highlights the need to reconsider the methods used to assess herb safety and efficacy. This will help physicians and healthcare professionals to provide considered advice to patients based upon documented evidence.
... Among these compounds' polyphenols, quercetins and Epigallocatechin gallate are the activators of the anti-aging gene Sirtuin 1 (Sirt 1) [35]. Sirtuin 1 is critical to the control of hypertension and preeclampsia [35,36]. Other Sirtuin 1 activators from plants or diets that do not contain Sirt 1 inhibitors promote Sirt 1 activators to accelerate hepatic caffeine metabolism to prevent T3D (Type 3 diabetes" is a term some people use to describe Alzheimer's disease) connected to various organ diseases in the developing world. ...
... Lower damage to body tissues can also take place, including: internal hemorrhaging; disruption of gas-filled organs like the swim bladder, and consequent damage to surrounding tissues. Single Gene Inactivation can occur with Implications to Diabetes and Multiple Organ Dysfunction Syndrome [6]. The animal may also receive injuries to its auditory system, with the ears themselves being damaged. ...
Underwater sound is very important to most fishes and invertebrates. Underwater sounds from both natural and human sources can have adverse effects upon aquatic animals, and especially fishes, and invertebrates. It is important to examine the effects of sound upon them, and especially the effects of sounds derived from human sources (anthropogenic sounds). It may be possible to introduce protective regulations to reduce their effects. Fishes and invertebrates can detect underwater sounds, and they use sound to obtain key information about the environment around them. They can also make sounds themselves, especially during their spawning. Sounds travel rapidly over great distances in water and can provide detailed information to these animals on the presence of prey, predators, and related species, while the overall acoustic scene provides them with key information about their environment. Anthropogenic sounds can be very harmful, and it is therefore important to deal with them. A succession of reports and scientific papers have emphasised the risks to these animals from exposure to man-made sounds or noise and will be mentioned in this paper, which also deals with the Criteria and Metrics for assessing the effects of underwater sound on fishes and invertebrates.
... For example, the role of the anti-aging gene Sirtuin 1 [2] may be critical to the survival of dairy cows, cattle and dairy buffalo. Sirtuin 1 [3] levels may need to be assessed with relevance key regulatory mechanisms and key gene functions that determine the molecular switch involved in the aging process [4,5] that may affect milk production and breeding programs. Heat and cold stress [6] affects Sirtuin 1 with core body temperature effects that may determine milk production and breeding of dairy cattle and buffalo. ...
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Animal growth is a coordinated developmental process that requires altering the expression of hundreds to thousands of genes to modify many biochemical and biological signaling cascades. The genetic analysis of economic traits and molecular breeding research are hotspots for animal husbandry and, in the case of Chinese dairy cattle, much progress has been made in recent years. Actually, the level of information of molecular events at the transcriptional, biochemical, hormonal, and metabolite levels underlying animal development process has increased considerably. The current review summarizes progress in research into the genetic basis of economic traits and molecular breeding of dairy cows, dual-purpose cattle and dairy buffalo, to better understand the molecular switch involved in development process with important consequences from a breeding point of view.
... SIRT-1 is an enzyme located primarily in the cell nucleus that deacetylates transcription factors that contribute to cellular regulation. The SIRT family comprises seven NAD + -dependent deacetylases which control the overall health of organisms through the regulation of pleiotropic metabolic pathways [160,161]. SIRT-1 is an important modulator of adipose tissue metabolism and its expression is higher in lean than obese subjects [162]. Of note, SIRT-1 inactivation is involved in lipid metabolism and VO [163]. ...
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Alzheimer’s disease (AD) is the most common type of dementia characterized by the deposition of amyloid beta (Aβ) plaques and tau-neurofibrillary tangles in the brain. Visceral obesity (VO) is usually associated with low-grade inflammation due to higher expression of pro-inflammatory cytokines by adipose tissue. The objective of the present review was to evaluate the potential link between VO and the development of AD. Tissue hypoxia in obesity promotes tissue injury, production of adipocytokines, and release of pro-inflammatory cytokines leading to an oxidative-inflammatory loop with induction of insulin resistance. Importantly, brain insulin signaling is involved in the pathogenesis of AD and lower cognitive function. Obesity and enlargement of visceral adipose tissue are associated with the deposition of Aβ. All of this is consonant with VO increasing the risk of AD through the dysregulation of adipocytokines which affect the development of AD. The activated nuclear factor kappa B (NF-κB) pathway in VO might be a potential link in the development of AD. Likewise, the higher concentration of advanced glycation end-products in VO could be implicated in the pathogenesis of AD. Taken together, different inflammatory signaling pathways are activated in VO that all have a negative impact on the cognitive function and progression of AD except hypoxia-inducible factor 1 which has beneficial and neuroprotective effects in mitigating the progression of AD. In addition, VO-mediated hypoadiponectinemia and leptin resistance may promote the progression of Aβ formation and tau phosphorylation with the development of AD. In conclusion, VO-induced AD is mainly mediated through the induction of oxidative stress, inflammatory changes, leptin resistance, and hypoadiponectinemia that collectively trigger Aβ formation and neuroinflammation. Thus, early recognition of VO by visceral adiposity index with appropriate management could be a preventive measure against the development of AD in patients with VO. Graphical Abstract
Diabetes Mellitus (DM) and Alzheimer's disease (AD) have been two of the most common chronic diseases affecting people worldwide. Type 2 DM (T2DM) is a metabolic disease depicted by insulin resistance, dyslipidemia, and chronic hyperglycemia while AD is a neurodegenerative disease marked by Amyloid β (Aβ) accumulation, neurofibrillary tangles aggregation, and tau phosphorylation. Various clinical, epidemiological, and lipidomics studies have linked those diseases claiming shared pathological pathways raising the assumption that diabetic patients are at an increased risk of developing AD later in their lives. Insulin resistance is the tipping point beyond where advanced glycation end (AGE) products and free radicals are produced leading to oxidative stress and lipid peroxidation. Additionally, different types of lipids are playing a crucial role in the development and the relationship between those diseases. Lipidomics, an analysis of lipid structure, formation, and interactions, evidently exhibits these lipid changes and their direct and indirect effect on Aβ synthesis, insulin resistance, oxidative stress, and neuroinflammation. In this review, we have discussed the pathophysiology of T2DM and AD, the interconnecting pathological pathways they share, and the lipidomics where different lipids such as cholesterol, phospholipids, sphingolipids, and sulfolipids contribute to the underlying features of both diseases. Understanding their role can be beneficial for diagnostic purposes or introducing new drugs to counter AD.
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International Scientist Lifetime Achievement Award 2022 On Engineering, Science and Medicine. This Lifetime Achievement Awards recognizes contributions over the whole of a career of Ian James Martins. Dr Ian James Martins is also the Outstanding Scientist Award 2022, International Scientist Awards 2022 (INSO AWARDS) on Engineering, Science and Medicine. ABCD Wall provide a live platform of the Life Journey and career: Video Program: Live platform YouTube:
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The number of COVID-19-associated nephropathies (COVAN) rapidly increased before the fourth wave of the COVID-19 pandemic. Similarities and common lesions with the HIV-associated nephropathy (HIVAN) remarkably affect mostly African Americans positive for the APOL1 risk variants; therefore, these cases must be prioritized in new targeted clinical trials.
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The anti-aging gene Sirtuin 1 has now major relevance to genetics and the fields of pharmacology, toxicology, neurosci¬ence, immunology, biochemistry and cell/molecular biology. Advances in anti-aging therapy are now essential to prevent mitochondrial apoptosis to promote longevity with the pre¬vention of accelerated ageing. Calorie restriction that main¬tains the anti-aging gens changes the core body temperature and promotes species longevity. Stress and calorie consump¬tion are sensitive to Sirt 1 function with relevance heat shock protein 70 metabolism and mitochondrial biogenesis. Sirt 1 regulation of the circadian rhythm mediates melatonin effects on core body temperature regulation and immune responses. Diet and fat are essential factors that determine species lon¬gevity with relevance to heat shock gene regulation and mi¬tochondrial disease in animals and man. Strenuous exercise to activate the cellular heat shock gene in animals and man should be carefully controlled to prevent magnesium deficien¬cy with relevance to immune disorders and mitophagy.
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Editorial Mental illness in Western communities has increased with the global depression crisis a major disorder in managing psychiatric disturbances. The association between diabetes and depression indicate that psychiatric disturbances such as schizophrenia and bipolar disorders are far greater in diabetic individuals than individuals in the general population. Stress and anxiety are closely associated with mental illness, behaviour and cognition disorders and these psychiatric disorders may be involved in the induction of neurodegeneration, organ disease and diabetes [1]. Interests in diet, lifestyle, stress and sleep factors have been the focus of many communities as factors that influence specific genes involved in the onset of depression and neurodegeneration and may be the primary cause of psychiatric disturbances in diabetic individuals. Epigenetic alterations in diabetes [2-5] induced by the environment [6] have become important to diabetes with post-transcriptional changes linked to various disease processes in diabetes. Diabetics have appetite dysregulation and therole of genes such as the anti-aging gene Sirtuin 1 (Sirt 1) regulated by magnesium [7] and unhealthy diets [8] has escalated that links depression and appetite control to be of major importance in the treatment of various psychiatric disturbances. Sirt 1 is connected to food intake, depression, schizophrenia, cognition, memory and learning [9-15] with research directed to maintain brain Sirt 1 activity such as magnesium therapy [7] to prevent neurodegeneration in diabetes (Figure 1). Recent interests in Type 3 diabetes [16,17] implicate Sirt 1 as the defective gene with relevance to appetite control and chronic disease. The hypothalamic-pituitary axis implicates the peptide apelinto be involved in the neuroendocrine system with central coordination between the brain and peripheral tissues (intestine, liver, kidney, heart). The interference of apelin by stress related disorders generates angiotensin II and inactivates nitric oxide (NO) metabolism with interference of Sirt 1 regulation of Nitric Oxide (NO) balance [18] relevant to appetite control, stroke and dementia [19] (Figure 1). Apelinergic system and appetite control are now important to diabetic treatment with close connection of the defective apelinergic system involved in brain NO production with relevance to NO induced post-transcriptional alterations [20]. Inactivation of NO metabolism (Figure 1) interferes with Sirt 1 role in epigenetic changes [6] associated with the induction of circadian rhythm abnormalities, mental illness, endocrine disease and appetite dysregulation [21-25]. Magnesium is involved in the release of NO [26,27] with magnesium deficiency connected to neurodegeneration, mental illness and cardiovascular disease [7]. NO is an intercellular messenger involved in signal transduction [28] in the brain and is intimately involved in synaptic plasticity with relevance to programmed cell death. Its role as a hormone [29] has become important and is closely associated with the neuroendocrine system [30-32]. The nature of low calorie diets that regulate Sirt 1 indicate its critical role in brain NO homeostasis important to hypothalamic function with relevance to appetite regulation and circadian rhythm disorders [22,23,25] in diabetes and various chronic diseases. Nutrigenomic diets [8] and the prevention of stress maintain Sirt 1 and brain NO balance that activate the neuroendocrine system [18] linked to appetite control and psychiatric conditions in diabetes and associated organ diseases. Drug therapy is essential for the maintenance of NO metabolism [33,34] in mental health disorders and an intact apelinergic system [19] is required to prevent psychiatric disturbances and peripheral organ disease. The use of nutrition and drug therapy is now connected to magnesium with magnesium signaling important in the prevention of NO toxicity and programmed cell death. The effects of magnesium therapy [35,36]
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Diet and lifestyle has become important to the maintenance of mitochondrial biogenesis that has become of major concern to chronic diseases. The anti-aging gene Sirtuin 1 (Sirt 1) is regulated by diet with high calorie diets involved in its downregulation. Under post-prandial conditions with increased fatty acids and glucose consumption the Sirt 1 regulation of suprachiasmatic nucleus (SCN) involved in the regulation of brain and liver amyloid beta metabolism [1] is reset with circadian rhythm alterations related to cholesterol efflux disturbances, amyloid beta aggregation and mitochondrial apoptosis [2-5]. Individuals with apolipo-protein E4 (apo E4) are more susceptible to mitochondrial apoptosis [6] when compared with apo E3 and related to the reduced liver amyloid beta clearance. Defective Sirt 1 in diabetes and Alzheimer's disease [1] involve hypercholes-terolemia and amyloid beta aggregation with induction of mitophagy and programmed cell death. Heat shock proteins (HSP) are now linked to obesity, cardiovascular disease, adiposity and Alzheimer's disease [7-9].
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Endothelial cells (ECs) express fibroblast growth factor (FGF) receptors and are metabolically active after treatment with FGF-23. It is not known if this effect is α-Klotho independent or mediated by humoral or endogenous endothelial α-Klotho. In the present study, we aimed to characterize EC α-Klotho expression within the human vascular tree and to investigate the potential role of α-Klotho in determining FGF-23 mediated EC regulation. Human tissue and ECs from various organs were used for immunohistochemistry and Western blot. Primary cultures of human aortic endothelial cells (HAECs) and human brain microvascular endothelial cells (HBMECs) were used to generate in vitro cell models. We found endogenous α-Klotho expression in ECs from various organs except in microvascular ECs from human brain. Furthermore, FGF-23 stimulated endothelial nitric oxide synthase (eNOS) expression, nitric oxide (NO) production, and cell proliferation in HAECs. Interestingly, these effects were not observed in our HBMEC model in vitro. High phosphate treatment and endothelial α-Klotho knockdown mitigated FGF-23 mediated eNOS induction, NO production, and cell proliferation in HAECs. Rescue treatment with soluble α-Klotho did not reverse endothelial FGF-23 resistance caused by reduced or absent α-Klotho expression in HAECs. These novel observations provide evidence for differential α-Klotho functional expression in the human endothelium and its presence may play a role in determining the response to FGF-23 in the vascular tree. α-Klotho was not detected in cerebral microvascular ECs and its absence may render these cells nonresponsive to FGF-23.
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Drug and endocrine therapy to delay the complications of obesity and diabetes has escalated with the use of chronic disease medications to improve therapy in the presence of ER stress induced mitophagy. Nutrient assessment in diabetes has increased to activate the heat shock gene Sirt 1 and to prevent ER stress that may be the critical to the prevention of drug induced toxicity, ER stress and mitophagy. Heat therapy may lead to inactivation of the heat shockgene Sirt 1 with inactivation of various critical drug and endocrine therapies essential for multiple organ dysfunction syndrome.
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Objective: To describe the pathophysiology associated with multiple organ dysfunction syndrome in children. Data sources: Literature review, research data, and expert opinion. Study selection: Not applicable. Data extraction: Moderated by an experienced expert from the field, pathophysiologic processes associated with multiple organ dysfunction syndrome in children were described, discussed, and debated with a focus on identifying knowledge gaps and research priorities. Data synthesis: Summary of presentations and discussion supported and supplemented by relevant literature. Conclusions: Experiment modeling suggests that persistent macrophage activation may be a pathophysiologic basis for multiple organ dysfunction syndrome. Children with multiple organ dysfunction syndrome have 1) reduced cytochrome P450 metabolism inversely proportional to inflammation; 2) increased circulating damage-associated molecular pattern molecules from injured tissues; 3) increased circulating pathogen-associated molecular pattern molecules from infection or endogenous microbiome; and 4) cytokine-driven epithelial, endothelial, mitochondrial, and immune cell dysfunction. Cytochrome P450s metabolize endogenous compounds and xenobiotics, many of which ameliorate inflammation, whereas damage-associated molecular pattern molecules and pathogen-associated molecular pattern molecules alone and together amplify the cytokine production leading to the inflammatory multiple organ dysfunction syndrome response. Genetic and environmental factors can impede inflammation resolution in children with a spectrum of multiple organ dysfunction syndrome pathobiology phenotypes. Thrombocytopenia-associated multiple organ dysfunction syndrome patients have extensive endothelial activation and thrombotic microangiopathy with associated oligogenic deficiencies in inhibitory complement and a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13. Sequential multiple organ dysfunction syndrome patients have soluble Fas ligand-Fas-mediated hepatic failure with associated oligogenic deficiencies in perforin and granzyme signaling. Immunoparalysis-associated multiple organ dysfunction syndrome patients have impaired ability to resolve infection and have associated environmental causes of lymphocyte apoptosis. These inflammation phenotypes can lead to macrophage activation syndrome. Resolution of multiple organ dysfunction syndrome requires elimination of the source of inflammation. Full recovery of organ functions is noted 6-18 weeks later when epithelial, endothelial, mitochondrial, and immune cell regeneration and reprogramming is completed.
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Prevalent chronic diseases such as cardiovascular disease, non alcoholic fatty liver disease (NAFLD) and neurodegenerative diseases have raised major concern with relevance to diabetes and the global problem for chronic diseases extending to various parts of the developing world. The role of various factors such as diet, environment, stress and lifestyle as important factors that regulate chronic disease progression have been explored with various studies that indicate major changes in unhealthy diets may assist with a delay in the acceleration of these chronic diseases. Drug therapy to stabilize insulin resistance and various chronic diseases that reverse cell senescence and apoptosis has been implemented in various global populations. The need to optimize drug therapy and improve therapeutic outcomes has become of major concern with relevance to alarming reports of drug-drug interactions or drug-disease interactions with relevance to the global chronic disease epidemic
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The rise in obesity and diabetes in various countries have reached epidemic proportions with the inability of the brain to regulate body weight and energy balance in the early part of life and related to neurodegenerative disease in these countries. Neurons in the brain become sensitive to Western diets with alterations in neurons that lead to brain circuitry disorders or feeding signals. In insulin resistance and neurodegenerative diseases the astrocyte-neuron interaction is defective in the brain and consumption of a Western diet does not allow neurons to metabolize glucose and fatty acids but instead leads to mitochondrial apoptosis and programmed neuron death. In the periphery in global communities liver steatosis can be reversible with hepatocyte mitochondria still able to metabolize fatty acids and glucose after consumption of a healthy low calorie diet but in the brain neuron mitochondria may not continue with mitochondrial biogenesis but continue to undergo apoptosis with neuron death.
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EDITORIAL In the United States and Europe the geriatric population (> 65 years) is expected to double by the year 2060 with the death rate in the European Union in the geriatric population to be greater than 80% when compared with individuals < 65 years [1,2]. Geriatrics are susceptible to the global increase in chronic diseases with diabetes and neurodegenerative disease predicted to effect and determine the increased death rate of the geriatric population in the next 40 years. A defect in a single gene versus multi gene effects may be responsible for accelerated aging connected to mitochondrial apoptosis [3] and programmed cell death with relevance to insulin resistance and the increased death rate in geriatrics. The United States population is composed of white Americans, black/African Americans, native Americans, Alaska natives, Asian Americans, native Hawaiians/pacific islanders and Hispanic/Latino Americans [4]. The defect in a gene that may cause mitochondrial apoptosis in all these individuals and connected to insulin resistance identifies the heat shock gene Sirtuin 1 (Sirt 1) to be defective in these populations [5].
Adipose tissue inflammation, characterized by augmented infiltration and altered polarization of macrophages, contributes to insulin resistance and its associated metabolic diseases. The NAD(+)-dependent deacetylase SIRT1 serves as a guardian against metabolic disorders in multiple tissues. To dissect the roles of SIRT1 in adipose tissues, metabolic phenotypes of mice with selective ablation of SIRT1 in adipocytes and myeloid cells were monitored. Compared to myeloid-specific SIRT1 depletion, mice with adipocyte-selective deletion of SIRT1 are more susceptible to diet-induced insulin resistance. The phenotypic changes in adipocyte-selective SIRT1 knockout mice are associated with an increased number of adipose-resident macrophages and their polarization toward the pro-inflammatory M1 subtype. Mechanistically, SIRT1 in adipocytes modulates expression and secretion of several adipokines, including adiponectin, MCP-1, and interleukin 4, which in turn alters recruitment and polarization of the macrophages in adipose tissues. In adipocytes, SIRT1 deacetylates the transcription factor NFATc1 and thereby enhances the binding of NFATc1 to the Il4 gene promoter. These findings suggest that adipocyte SIRT1 controls systemic glucose homeostasis and insulin sensitivity via the cross talk with adipose-resident macrophages.