The Dynamics and Plasticity of Epigenetics in Diabetic Kidney Disease: Therapeutic Applications Vis-à-Vis

Chronic kidney disease (CKD) refers to the phenomenon of progressive decline in the glomerular filtration rate accompanied by adverse consequences, including fluid retention, electrolyte imbalance, and an increased cardiovascular risk compared to those with normal renal function. The triggers for the irreversible renal function deterioration are multifactorial, and diabetes mellitus serves as a major contributor to the development of CKD, namely diabetic kidney disease (DKD). Recently, epigenetic dysregulation emerged as a pivotal player steering the progression of DKD, partly resulting from hyperglycemia-associated metabolic disturbances, rising oxidative stress, and/or uncontrolled inflammation. In this review, we describe the major epigenetic molecular mechanisms, followed by summarizing current understandings of the epigenetic alterations pertaining to DKD. We highlight the epigenetic regulatory processes involved in several crucial renal cell types: Mesangial cells, podocytes, tubular epithelia, and glomerular endothelial cells. Finally, we highlight epigenetic biomarkers and related therapeutic candidates that hold promising potential for the early detection of DKD and the amelioration of its progression.

Toward the Decipherment of Molecular Interactions in the Diabetic Brain

Diabetes mellitus (DM) has been associated with cognitive complications in the brain resulting from acute and chronic metabolic disturbances happening peripherally and centrally. Numerous studies have reported on the morphological, electrophysiological, biochemical, and cognitive changes in the brains of diabetic individuals. The detailed pathophysiological mechanisms implicated in the development of the diabetic cognitive phenotype remain unclear due to intricate molecular changes evolving over time and space. This review provides an insight into recent advances in understanding molecular events in the diabetic brain, focusing on cerebral glucose and insulin uptake, insulin action in the brain, and the role of the brain in the regulation of glucose homeostasis. Fully competent mitochondria are essential for energy metabolism and proper brain function; hence, the potential contribution of mitochondria to the DM-induced impairment of the brain is also discussed.

The microRNA-455 Null Mouse Has Memory Deficit and Increased Anxiety, Targeting Key Genes Involved in Alzheimer’s Disease

The complete molecular mechanisms underlying the pathophysiology of Alzheimer’s disease (AD) remain to be elucidated. Recently, microRNA-455-3p has been identified as a circulating biomarker of early AD, with increased expression in post-mortem brain tissue of AD patients. MicroRNA-455-3p also directly targets and down-regulates APP, with the overexpression of miR-455-3p suppressing its toxic effects. Here, we show that miR-455-3p expression decreases with age in the brains of wild-type mice. We generated a miR-455 null mouse utilising CRISPR-Cas9 to explore its function further. Loss of miR-455 resulted in increased weight gain, potentially indicative of metabolic disturbances. Furthermore, performance on the novel object recognition task diminished significantly in miR-455 null mice (p = 0.004), indicating deficits in recognition memory. A slight increase in anxiety was also captured on the open field test. BACE1 and TAU were identified as new direct targets for miR-455-3p, with overexpression of miR-455-3p leading to a reduction in the expression of APP, BACE1 and TAU in neuroblastoma cells. In the hippocampus of miR-455 null mice at 14 months of age, the levels of protein for APP, BACE1 and TAU were all increased. Such findings reinforce the involvement of miR-455 in AD progression and demonstrate its action on cognitive performance.

Effect of oat supplementation interventions on cardiovascular disease risk markers: a systematic review and meta-analysis of randomized controlled trials

Purpose Oat supplementation interventions (OSIs) may have a beneficial effect on cardiovascular disease (CVD) risk. However, dietary background can modulate such effect. This systematic review assesses the effects of OSIs on CVD risk markers among adults, accounting for different dietary backgrounds or control arms. Methods We included randomized clinical trials (RCTs) that assessed the effect of oat, oat beta-glucan-rich extracts or avenanthramides on CVD risk markers. Results Seventy-four RCTs, including 4937 predominantly hypercholesterolemic, obese subjects, with mild metabolic disturbances, were included in the systematic review. Of these, 59 RCTs contributed to the meta-analyses. Subjects receiving an OSI, compared to control arms without oats, had improved levels of total cholesterol (TC) [weighted mean difference and (95% CI) − 0.42 mmol/L, (− 0.61; − 0.22)], LDL cholesterol [− 0.29 mmol/L, (− 0.37; − 0.20)], glucose [− 0.25 nmol/L, (− 0.36; − 0.14)], body mass index [− 0.13 kg/m2, (− 0.26; − 0.01)], weight [− 0.94 kg, (− 1.84: − 0.05)], and waist circumference [− 1.06 cm, (− 1.85; − 0.27)]. RCTs on inflammation and/or oxidative stress markers were scarce and with inconsistent findings. RCTs comparing an OSI to heterogeneous interventions (e.g., wheat, eggs, rice, etc.), showed lowered levels of glycated haemoglobin, diastolic blood pressure, HDL cholesterol and apolipoprotein B. The majority of included RCTs (81.1%) had some concerns for risk of bias. Conclusion Dietary OSIs resulted in lowered levels of blood lipids and improvements in anthropometric parameters among participants with predominantly mild metabolic disturbances, regardless of dietary background or control. Further high-quality trials are warranted to establish the role of OSIs on blood pressure, glucose homeostasis and inflammation markers.

Apolipoprotein E and sex modulate fatty acid metabolism in a prospective observational study of cognitive decline

Background Fatty acids play prominent roles in brain function as they participate in structural, metabolic and signaling processes. The homeostasis of fatty acids and related pathways is known to be impaired in cognitive decline and dementia, but the relationship between these metabolic disturbances and common risk factors, namely the ɛ4 allele of the apolipoprotein E (ApoE-ɛ4) gene and sex, remains elusive. Methods In order to investigate early alterations associated with cognitive decline in the fatty acid-related serum metabolome, we here applied targeted metabolomics analysis on a nested case-control study (N=368), part of a prospective population cohort on dementia. Results When considering the entire study population, circulating levels of free fatty acids, acyl-carnitines and pantothenic acid were found to be increased among those participants who had greater odds of cognitive decline over a 12-year follow-up. Interestingly, stratified analyses indicated that these metabolomic alterations were specific for ApoE-ɛ4 non-carriers and women. Conclusions Altogether, our results highlight that the regulation of fatty acids and related metabolic pathways during ageing and cognitive decline depends on complex inter-relationships between the ApoE-ε4 genotype and sex. A better understanding of the ApoE-ɛ4 and sex dependent modulation of metabolism is essential to elucidate the individual variability in the onset of cognitive decline, which would help develop personalized therapeutic approaches.

Pre-treatment and continuous administration of simvastatin during sepsis improve metabolic parameters and prevent CNS injuries in survivor rats

Sepsis causes overproduction of inflammatory cytokines, organ dysfunction and cognitive impairment in survivors. In addition to inflammation, metabolic changes occur according to the stage and severity of the disease. Understanding the role and place of metabolic disturbances in the pathophysiology of sepsis is essential to evaluate the framework of septic patients, predict the syndrome progress and define treatment strategies. We investigated the effect of simvastatin on the disease time course and on metabolic alterations, especially with respect to their possible consequences in the CNS of surviving rats. The animals of this study were weighed daily and followed for 10 days to determine the survival rate. In the first experiment, control or CLP-animals were randomized in 24 h, 48 h and 10 days after septic induction, for bacterial load determination and, quantification of cytokines. In the second experiment, control or CLP-animals were treated or not with simvastatin and randomized in the same three time points for cytokines quantification and assessment of their body metabolism and locomotor activity (at 48 h and 10 days), as well as the evaluation of cytoarchitecture and astrogliosis (at 10 days). The CLP-rats treated with simvastatin showed a reduction in plasma cytokines and improvement in metabolic parameters and locomotor activity, followed by minor alterations compatible with apoptosis and astrogliosis in the hippocampus and prefrontal cortex. These results suggest that the anti-inflammatory effect of simvastatin plays a crucial role in restoring energy production, maintaining a hypermetabolic state necessary for the recovery and survival of these CLP-rats.

Young APPKI NL-G-F/NL-G-F mice display high-fat diet-induced metabolic disturbances and specific disorders associated with brain energy homeostasis.

Aim: Type 2 diabetes mellitus (T2DM) is an increased risk factor for Alzheimer's disease (AD); however, the relationship between the two conditions is controversial. High-fat diet (HFD) causes cognitive impairment with/without Aβ accumulation in middle-aged or aged transgenic (Tg) and knock-in (KI) AD mouse models, except for metabolic disorders, which commonly occur in all mice types. Alternatively, whether HFD in early life impacts energy metabolism and neurological phenotypes in young AD mouse models remains unknown. In the present study, we examined the effects of HFD on young APPKI NL-G-F/NL-G-F mice, one of the novel knock-in (KI)-AD mouse models. Methods: The mice were categorized by diet into two experimental groups, normal diet (ND) and HFD. Four-week-old WT and APPKI NL-G-F/NL-G-F mice were fed ND or HFD for nine weeks. Both types of mice on ND and HFD were examined during young adulthood. Results: HFD causes T2DM-related metabolic disturbances in young WT and APPKI NL-G-F/NL-G-F mice and specific impairment of brain energy homeostasis only in young APPKI NL-G-F/NL-G-F mice. However, HFD-induced metabolic dysfunctions had no impact on behaviors, Aβ levels, and specific IRS1 modifications in both young APPKI NL-G-F/NL-G-F mice and young WT mice. Conclusion: HFD in early life is effective in causing metabolic disturbances in young WT and APPKI NL-G-F/NL-G-F mice but is ineffective in inducing neurological disorders in young mice, which suggests that the aging effects along with long-term HFD cause neurological alterations.

D-allulose ameliorates adiposity through the AMPK-SIRT1-PGC-1α pathway in HFD-induced SD rats

Background: Adiposity is a major health-risk factor, and D-allulose has beneficial effects on adiposity-related metabolic disturbances. However, the modes of action underlying anti-hyperglycemic and hypolipidemic activity are partly understood. Objective: This study investigated the in vivo and in vitro effects of D-allulose involved in adipogenesis and activation of the AMPK/SIRT1/PGC-1α pathway in high-fat diet (HFD)-fed rats. Design: In this study, 8-week-old male SD (Sprague Dawley) rats were divided into five groups (n = 8/group), (1) Control (chow diet, 3.5%); (2) 60% HFD; (3) 60% HFD supplemented with allulose powder (AP) at 0.4 g/kg; (4) 60% HFD supplemented with allulose liquid (AL) at 0.4 g/kg; (5) 60% HFD supplemented with glucose (AL) at 0.4 g/kg. All the group received the product through oral gavage for 6 weeks. Control and HFD groups were gavaged with double-distilled water. Results: Rats receiving AP and AL showed reduced body weight gain and fat accumulation in HFD-fed rats. Also, supplementation of AL/AP regulated the cytokine secretion and recovered biochemical parameters to alleviate metabolic dysfunction and hepatic injury. Additionally, AL/AP administration improved adipocyte differentiation via regulation of the PPARγ and C/EBPα signaling pathway and adipogenesis-related genes owing to the combined effect of the AMPK/SIRT1 pathway. Furthermore, AL/AP treatment mediated PGC-1α expression triggering mitochondrial genesis via activating the AMPK phosphorylation and SIRT1 deacetylation activity in adipose tissue. Conclusion: The anti-adiposity activity of D-allulose is observed on a marked alleviation in adipogenesis and AMPK/SIRT1/PGC-1α deacetylation in the adipose tissue of HFD-fed rat.

Chronological Appearance of Endocrine and Metabolic Dysfunctions Induced by an Unhealthy Diet in Rats

Background and Objectives: The work was aimed to determine the chronological sequence of events triggered by a fructose-rich diet (FRD) (10% w/v in the drinking water) in normal rats. Material and Methods: Serum parameters, liver and islet markers of metabolism, inflammation and oxidative stress were determined weekly for 21 days. Results: At the end of the first week, rats fed with a FRD showed an early increase in circulating triglycerides, fat liver deposit, and enzymatic activity of liver glucokinase and glucose-6-phosphate dehydrogenase (G6P-DH). After two weeks of such a diet, liver glucose-6-phosphatase (G6Pase) activity and liver oxidative stress markers were significantly increased. Liver sterol regulatory element-binding protein 1c (SREBP1c) mRNA also increased in the second week while their target genes fatty acid synthase (FAS) and glycerol-3-phosphate dehydrogenase (GPAT) enhanced their expression at the third week. Liver and pancreatic inflammation markers also enhanced their gene expression in the last week of treatment. Whereas both control and FRD rats remained normoglycemic throughout the entire period of treatment, blood insulin levels were significantly higher in FRD animals at the third week, thereby evidencing an insulin-resistant state (higher HOMA-IR, HOMA-B and HIS indexes). Pancreatic islets isolated from rats fed with a FRD for 3 weeks also increased glucose-induced insulin secretion (8.3 and 16.7 mM). Conclusions: FRD induces asynchronous changes involving early hypertriglyceridemia together with intrahepatic lipid deposit and metabolic disturbances from week one, followed by enhanced liver oxidative stress, liver and pancreas inflammation, pancreatic β-cell dysfunction, and peripheral insulin-resistance registered at the third week. Knowledge of time-course adaptation mechanisms involved in our rat model could be helpful in developing appropriate strategies to prevent the progression from prediabetes to Type 2 diabetes (T2D) triggered by unhealthy diets.

Rhinoceros Serum microRNAs: Identification, Characterization, and Evaluation of Potential Iron Overload Biomarkers

Iron overload disorder (IOD) in critically endangered Sumatran (Dicerorhinus sumatrensis) and black (Diceros bicornis) rhinoceros is an over-accumulation of iron in organs which may exacerbate other diseases and indicate metabolic disturbances. IOD in rhinos is not well understood and diagnostics and therapeutics are limited in effectiveness. MicroRNAs (miRNAs) are small non-coding RNAs capable of altering protein synthesis. miRNA expression responds to physiological states and could serve as the basis for development of diagnostics and therapeutics. This study aimed to identify miRNAs differentially expressed among healthy rhinos and those afflicted with IOD or other diseases (“unhealthy”), and assess expression of select miRNAs to evaluate their potential as biomarkers of IOD. miRNAs in serum of black (n = 11 samples; five individuals) and Sumatran (n = 7 samples; four individuals) rhinos, representing individuals categorized as healthy (n = 9), unhealthy (n = 5), and afflicted by IOD (n = 3) were sequenced. In total, 715 miRNAs were identified, of which 160 were novel, 131 were specific to black rhinos, and 108 were specific to Sumatran rhinos. Additionally, 95 miRNAs were specific to healthy individuals, 31 specific to unhealthy, and 63 were specific to IOD individuals. Among healthy, unhealthy, and IOD states, 21 miRNAs were differentially expressed (P ≤ 0.01). Five known miRNAs (let-7g, miR-16b, miR-30e, miR-143, and miR-146a) were selected for further assessment via RT-qPCR in serum from black (n = 61 samples; seven individuals) and Sumatran (n = 38 samples; five individuals) rhinos. let-7g, miR-30e, and miR-143 all showed significant increased expression (P ≤ 0.05) during IOD (between 1 and 2 years prior to death) and late IOD (within 1 year of death) compared to healthy and unhealthy individuals. miR-16b expression increased (P ≤ 0.05) in late IOD, but was not different among IOD, healthy, and unhealthy states (P > 0.05). Expression of miR-146a increased in IOD and late IOD as compared to unhealthy samples (P ≤ 0.05) but was not different from the healthy state (P > 0.05). Selected serum miRNAs of black and Sumatran rhinos, in particular let-7g, miR-30e, and miR-143, could therefore provide a tool for advancing rhino IOD diagnostics that should be further investigated.