Postnatal Consumption of Black Bean Powder Protects against Obesity and Dyslipidemia in Male Adult Rat Offspring from Obese Pregnancies.

The adverse influence of maternal obesity on offspring metabolic health throughout the life-course is a significant public health challenge with few effective interventions. We examined if black bean powder (BBP) supplementation to a high-calorie maternal pregnancy diet or a postnatal offspring diet could offer protection against the metabolic programming of metabolic disease risk in adult offspring. Female Sprague Dawley rats were randomly assigned to one of three diets (n = 10/group) for a 3-week pre-pregnancy period and throughout gestation and lactation: (i) a low-caloric control diet (CON); (ii) a high-caloric obesity-inducing diet (HC); or (iii) the HC diet with 20% black bean powder (HC-BBP). At weaning [postnatal day (PND) 21], one male pup from each dam was weaned onto the CON diet throughout the postnatal period until adulthood (PND120). In addition, a second male from the HC group only was weaned onto the CON diet supplemented with BBP (CON-BBP). Thus, based on the maternal diet exposure and offspring postnatal diet, four experimental adult offspring groups were compared: CON/CON, HC/CON, HC-BPP/CON, and HC/CON-BBP. On PND120, blood was collected for biochemical analysis (e.g., lipids, glycemic control endpoints, etc.), and livers were excised for lipid analysis (triglycerides [TG] and cholesterol) and the mRNA/protein expression of lipid-regulatory targets. Compared with the CON/CON group, adult offspring from the HC/CON group exhibited a higher (p < 0.05) body weight (BW) (682.88 ± 10.67 vs. 628.02 ± 16.61 g) and hepatic TG (29.55 ± 1.31 vs. 22.86 ± 1.85 mmol/g). Although maternal BBP supplementation (HC-BBP/CON) had little influence on metabolic outcomes, the consumption of BBP in the postnatal period (HC/CON-BBP) lowered hepatic TG and cholesterol compared with the other treatment groups. Reduced hepatic TG in the HC/CON-BBP was likely associated with lower postnatal BW gain (vs. HC/CON), lower mRNA and protein expression of hepatic Fasn (vs. HC/CON), and lower serum leptin concentration (vs. CON/CON and HC groups). Our results suggest that the postnatal consumption of a black-bean-powder-supplemented diet may protect male rat offspring against the programming of obesity and dyslipidemia associated with maternal obesity. Future work should investigate the bioactive fraction of BBP responsible for the observed effect.

Endocrine Responses to Heated Resistance Exercise in Men and Women.

ABSTRACT: Pryor, JL, Sweet, DK, Rosbrook, P, Qiao, J, Looney, DP, Mahmood, S, and Rideout, T. Endocrine responses to heated resistance exercise in men and women. J Strength Cond Res 38(7): 1248-1255, 2024-We examined the endocrine responses of 16 (female = 8) resistance trained volunteers to a single bout of whole-body high-volume load resistance exercise in hot (HOT; 40° C) and temperate (TEMP; 20° C) environmental conditions. Thermoregulatory and heart rate (HR) data were recorded, and venous blood was acquired before and after resistance exercise to assess serum anabolic and catabolic hormones. In men, testosterone increased after resistance exercise in HOT and TEMP ( p < 0.01), but postexercise testosterone was not different between condition ( p = 0.51). In women, human growth hormone was different between condition at pre-exercise ( p = 0.02) and postexercise ( p = 0.03). After controlling for pre-exercise values, the between-condition postexercise difference was abolished ( p = 0.16). There were no differences in insulin-like growth factor-1 for either sex ( p ≥ 0.06). In women, cortisol increased from pre-exercise to postexercise in HOT ( p = 0.04) but not TEMP ( p = 0.19), generating a between-condition difference at postexercise ( p < 0.01). In men, cortisol increased from pre-exercise to postexercise in HOT only ( p < 0.01). Rectal temperature increased to a greater extent in HOT compared with TEMP in both men ( p = 0.01) and women ( p = 0.02). Heart rate increased after exercise under both conditions in men and women ( p = 0.01), but only women experience greater postexercise HR in HOT vs. TEMP ( p = 0.04). The addition of heat stress to resistance exercise session did not overtly shift the endocrine response toward an anabolic or catabolic response. When acute program variables are prescribed to increase postresistance exercise anabolic hormones, adding heat stress is not synergistic but does increase physiologic strain (i.e., elevated HR and rectal temperature).

Evaluation of Phosphorus Storage and Performance of Broilers Using Phytase Synthetic Enzyme.

Phytic acid is a stored form of phosphorus in cereals, 65 to 70% of phosphorus in plant sources is phytate, and broilers are only able to use part of the phosphorus in plant sources. To meet the needs of chickens, it is necessary to use other artificial resources, which not only impose part of the cost of the breeding period because of its presence in the manure but is one of the factors polluting the environment. This study aimed to use different levels of phytase enzyme to reduce dietary phosphorus levels. 600 Ross 308 broilers were used in this experiment with five treatments and six replications, and in each replication, 20 chickens were used in a completely randomized design (CRD). Experimental treatments include 1) basal diet (control) 2) basal diet with 15% less phosphorus 3) basal diet with 15% less phosphorus + 1250 (FTU) phytase enzyme 4) basal diet with 15% less phosphorus + 2500 (FTU) phytase enzyme 5) basal diet with 15% less phosphorus + 5000 (FTU) phytase enzyme. The evaluated traits included weekly feed intake, weekly weight gain, feed conversion ratio, carcass characteristics, ash, calcium, and bone phosphorus. The use of phytase enzyme in different diets had no significant effect on food intake, weight gain, and feed conversion ratio (P>0.05). However, the use of phytase in different diets significantly affected the percentage of Gizzard, Heart, Liver, Proventriculus, and Spleen (P<0.05). The most changes were the increase in the ratio of feed intake and weight gain in the fourth week compared to the third week so that the changes in the ratio of feed intake ranged from 1.85 to 1.91, and this ratio for weight gain also ranged from 3.12 to 3.86 was recorded, and the lowest feed conversion ratio was obtained at the same age. The percentage of raw ash in broiler chickens was significantly increased by adding dietary phytase. The lowest amount of ash, calcium, and phosphorus belonged to the second group (diets with low phosphorus and no enzyme). The difference between the other groups and the control was not significant. Feed intake, weight gain, and feed conversion ratio with the addition of phytase enzyme were not affected by phosphorus reduction and had no significant effect on carcass characteristics. Environmental pollution can be prevented by reducing the level of dietary phosphorus and reducing excreted phosphorus.

Correlation of rs35753505 polymorphism in Neuregulin 1 gene with psychopathology and intelligence of people with schizophrenia.

BACKGROUND AND AIM: Schizophrenia is one of the most severe psychiatric disorders. About 0.5 to 1% of the world's population suffers from this non-Mendelian disorder. Environmental and genetic factors seem to be involved in this disorder. In this article, we investigate the alleles and genotypic correlation of mononucleotide rs35753505 polymorphism of Neuregulin 1 (NRG1), one of the selected genes of schizophrenia, with psychopathology and intelligence. MATERIALS AND METHODS: 102 independent and 98 healthy patients participated in this study. DNA was extracted by the salting out method and the polymorphism (rs35753505) were amplified by polymerase chain reaction (PCR). Sanger sequencing was performed on PCR products. Allele frequency analysis was performed using COCAPHASE software, and genotype analysis was performed using Clump22 software. RESULTS: According to our study's statistical findings, all case samples from the three categories of men, women, and overall participants significantly differed from the control group in terms of the prevalence of allele C and the CC risk genotype. The rs35753505 polymorphism significantly raised Positive and Negative Syndrome Scale (PANSS) test results, according to a correlation analysis between the two variables. However, this polymorphism led to a significant decrease in overall intelligence in case samples compared to control samples. CONCLUSION: In this study, it seems that the rs35753505 polymorphism of NRG1 gene has a significant role in the sample of patients with schizophrenia in Iran and also in psychopathology and intelligence disorders.

Maternal Pea Protein Intake Provides Sex-Specific Protection against Dyslipidemia in Offspring from Obese Pregnancies.

Increased consumption of dietary pulse protein has been shown to assist in body weight regulation and improve a range of metabolic health outcomes. We investigated if the exchange of casein for yellow pea protein (YPPN) in an obese-inducing maternal diet throughout pregnancy and lactation offered protection against obesity and dyslipidemia in offspring. Sixty female Sprague Dawley rats were fed a low-calorie control diet (CON), a high-caloric obesity-inducing diet (with casein protein (CP), HC-CP), or an isocaloric/macronutrient-matched HC diet supplemented with YPPN isolate (HC-PPN) in pre-pregnancy, gestation, and lactation. Body weight (BW) and metabolic outcomes were assessed in male and female offspring at weaning and in adulthood after consuming the CON diet in the postnatal period. Consumption of the HC-PPN diet did not protect against maternal obesity but did improve reproductive success compared with the HC-CP group (72.7% versus 43.7%) and reduced total energy, fat, and protein in maternal milk. Male, but not female, offspring from mothers fed the HC-CP diet demonstrated hyperphagia, obesity, dyslipidemia, and hepatic triglyceride (TG) accumulation as adults compared with CON offspring. Isocaloric exchange of CP for YPPN in a high-calorie obese-inducing diet did not protect against obesity but did improve several aspects of lipid metabolism in adult male offspring including serum total cholesterol, LDL/VLDL cholesterol, triglycerides (TGs), and hepatic TG concentration. Our results suggest that the exchange of CP for YPPN in a maternal obese-inducing diet selectively protects male offspring from the malprogramming of lipid metabolism in adulthood.

Trace elements-based Auroshell gold@hematite nanostructure: Green synthesis and their hyperthermia therapy.

Hyperthermia is an additional treatment method to radiation therapy/chemotherapy, which increases the survival rate of patients without side effects. Nowadays, Auroshell nanoparticles have attracted much attention due to their precise control over heat use for medical purposes. In this research, iron/gold Auroshell nanoparticles were synthesised using green nanotechnology approach. Auroshell gold@hematite nanoparticles were synthesised and characterised with rosemary extract in one step and the green synthesised nanoparticles were characterised by X-ray powder diffraction, SEM, high-resolution transmission electron microscopy, and X-ray photoelectron spectroscopy analysis. Cytotoxicity of Auroshell iron@gold nanoparticles against normal HUVEC cells and glioblastoma cancer cells was evaluated by 2,5-diphenyl-2H-tetrazolium bromide method, water bath hyperthermia, and combined method of water bath hyperthermia and nano-therapy. Auroshell gold@hematite nanoparticles with minimal toxicity are safe against normal cells. The gold shell around the magnetic core of magnetite caused the environmental and cellular biocompatibility of these Auroshell nanoparticles. These magnetic nanoparticles with targeted control and transfer to the tumour tissue led to uniform heating of malignant tumours as the most efficient therapeutic agent.

Maternal pea fiber supplementation to a high calorie diet in obese pregnancies protects male offspring from metabolic dysfunction in adulthood.

We investigated the influence of maternal yellow-pea fiber supplementation in obese pregnancies on offspring metabolic health in adulthood. Sixty newly-weaned female Sprague-Dawley rats were randomized to either a low-calorie control diet (CON) or high calorie obesogenic diet (HC) for 6-weeks. Obese animals were then fed either the HC diet alone or the HC diet supplemented with yellow-pea fiber (HC + FBR) for an additional 4-weeks prior to breeding and throughout gestation and lactation. On postnatal day (PND) 21, 1 male and 1 female offspring from each dam were weaned onto the CON diet until adulthood (PND 120) for metabolic phenotyping. Adult male, but not female, HC offspring demonstrated increased body weight and feed intake vs CON offspring, however no protection was offered by maternal FBR supplementation. HC male and female adult offspring demonstrated increased serum glucose and insulin resistance (HOMA-IR) compared with CON offspring. Maternal FBR supplementation improved glycemic control in male, but not female offspring. Compared with CON offspring, male offspring from HC dams demonstrated marked dyslipidemia (higher serum cholesterol, increased number of TG-rich lipoproteins, and smaller LDL particles) which was largely normalized in offspring from HC + FBR mothers. Male offspring born to obese mothers (HC) had higher hepatic TG, which tended to be lowered (p = 0.07) by maternal FBR supplementation.Supplementation of a maternal high calorie diet with yellow-pea fiber in prepregnancy and throughout gestation and lactation protects male offspring from metabolic dysfunction in the absence of any change in body weight status in adulthood.

Advances in Biosensing of Chemical Food Contaminants Based on the MOFs-Graphene Nanohybrids.

Food safety issue is becoming an international challenge for human health owing to the presence of contaminants. In this context, reliable, rapid, and sensitive detecting technology is extremely demanded to establish food safety assurance systems. MOFs (Metal-organic frameworks) are a new type of porous crystalline material with particular physical and chemical characteristics presented in food safety requirements. (Bio)sensors driven MOF materials have emerged as a promising alternative and complementary analytical techniques, owing to their great specific area, high porosity, and uniform and fine-tunable pore buildings. Nevertheless, the insufficient stability and electrical conductivity of classical MOFs limit their utilization. Employing graphene-derived nanomaterials with high functional elements as patterns for the MOF materials not only improves the structural instability and poor conductivity but also impedes the restacking and aggregation between graphene layers, thus significantly extending the MOFs application. A review of MOFs-graphene-based material used in food contamination detection is urgently needed for encouraging the advance of this field. Herein, this paper systematically outlines current breakthroughs in MOF-graphene-based nanoprobes, outlines their principles, and illustrates their employments in identifying mycotoxins, heavy metal ions, pathogens, antibiotics, and pesticides, referring to their multiplexing and sensitivity ability. The challenges and limitations of applying MOF-graphene composite for precise and efficient assessment of food were also debated. This paper would maybe offer some inspired concepts for an upcoming study on MOF-based composites in the food security context.

PCSK9 pathway-noncoding RNAs crosstalk: Emerging opportunities for novel therapeutic approaches in inflammatory atherosclerosis.

A variety of mechanisms contribute to the occurrence and development of inflammatory atherosclerosis (IA), resulting in cardiovascular disease. PCSK9 (proprotein convertase subtilisin/ kexin type 9) has now been recognized as a key player in the pathophysiology of atherosclerosis. Following PCSK9 activation, LDL receptors (LDLR) are degraded and as a result, LDL cholesterol (LDLC) levels are increased. Increasing evidence reports that the PCSK9 axis mediates IA through different pathways, such as LDLR, LOX1, NF-kB, and TLR4. In recent years, PCSK9 pathway dysregulation has been identified as one of the fundamental mechanisms involved in IA. Recently, the importance of epigenetic factors, in particular, in non-coding RNAs, including miRNAs and long ncRNAs (lncRNAs) as well as circular RNAs (circRNAs) in the regulation of physiological and pathological events has received great attention. In this regard, an expanding body of research has revealed that different ncRNAs play important roles in the progression of inflammatory atherosclerosis through targeting genes related to the PCSK9 pathway at the post-transcriptional level. Of importance, the current study aimed to review the relationship between the various ncRNAs and PCSK9 pathway to identify the molecular mechanisms underlying IA pathogenesis as well as to introduce the novel PCSK9 pathway-related therapeutic interventions in combating IA.

Aptasensor Based on Microfluidic for Foodborne Pathogenic Bacteria and Virus Detection: A Review.

In today's world, which is entangled with numerous foodborne pathogenic bacteria and viruses, it appears to be essential to rethink detection methods of these due to the importance of food safety in our lives. The vast majority of detection methods for foodborne pathogenic bacteria and viruses have suffered from sensitivity and selectivity due to the small size of these pathogens. Besides, these types of sensing approaches can improve on-site detection platforms in the fields of food safety. In recent, microfluidics systems as new emerging types of portable sensing approaches can introduce efficient and simple biodevice by integration with several analytical methods such as electrochemical, optical and colorimetric techniques. Additionally, taking advantage of aptamer as a selective bioreceptor in the sensing of microfluidics system has provided selective, sensitive, portable and affordable sensing approaches. Furthermore, some papers use increased data transferability ability and computational power of these sensing platforms by exploiting smartphones. In this review, we attempted to provide an overview of the current state of the recent aptasensor based on microfluidic for screening of foodborne pathogenic bacteria and viruses. Working strategies, benefits and disadvantages of these sensing approaches are briefly discussed.

Recent Developments in Artificial Intelligence-Based Techniques for Prostate Cancer Detection: A Scoping Review.

Artificial intelligence (AI) techniques can contribute to the early diagnosis of prostate cancer. Recently, there has been a sharp increase in the literature on AI techniques for prostate cancer diagnosis. This review article presents a summary of the AI methods that detect and diagnose prostate cancer using different medical imaging modalities. Following the PRISMA-ScR principle, this review covers 69 studies selected from 1441 searched papers published in the last three years. The application of AI methods reported in these articles can be divided into three broad categories: diagnosis, grading, and segmentation of tissues that have prostate cancer. Most of the AI methods leveraged convolutional neural networks (CNNs) due to their ability to extract complex features. Some studies also reported traditional machine learning methods, such as support vector machines (SVM), decision trees for classification, LASSO, and Ridge regression methods for features extraction. We believe that the implementation of AI-based tools will support clinicians to provide better diagnosis plans for prostate cancer.

A Scoping Review to Find Out Worldwide COVID-19 Vaccine Hesitancy and Its Underlying Determinants.

BACKGROUND: The current crisis created by the coronavirus pandemic is impacting all facets of life. Coronavirus vaccines have been developed to prevent coronavirus infection and fight the pandemic. Since vaccines might be the only way to prevent and stop the spread of coronavirus. The World Health Organization (WHO) has already approved several vaccines, and many countries have started vaccinating people. Misperceptions about vaccines persist despite the evidence of vaccine safety and efficacy. OBJECTIVES: To explore the scientific literature and find the determinants for worldwide COVID-19 vaccine hesitancy as reported in the literature. METHODS: PRISMA Extension for Scoping Reviews (PRISMA-ScR) guidelines were followed to conduct a scoping review of literature on COVID-19 vaccine hesitancy and willingness to vaccinate. Several databases (e.g., MEDLINE, EMBASE, and Google Scholar) were searched to find relevant articles. Intervention- (i.e., COVID-19 vaccine) and outcome- (i.e., hesitancy) related terms were used to search in these databases. The search was conducted on 22 February 2021. Both forward and backward reference lists were checked to find further studies. Three reviewers worked independently to select articles and extract data from selected literature. Studies that used a quantitative survey to measure COVID-19 vaccine hesitancy and acceptance were included in this review. The extracted data were synthesized following the narrative approach and results were represented graphically with appropriate figures and tables. RESULTS: 82 studies were included in this scoping review of 882 identified from our search. Sometimes, several studies had been performed in the same country, and it was observed that vaccine hesitancy was high earlier and decreased over time with the hope of vaccine efficacy. People in different countries had varying percentages of vaccine uptake (28-86.1%), vaccine hesitancy (10-57.8%), vaccine refusal (0-24%). The most common determinants affecting vaccination intention include vaccine efficacy, vaccine side effects, mistrust in healthcare, religious beliefs, and trust in information sources. Additionally, vaccination intentions are influenced by demographic factors such as age, gender, education, and region. CONCLUSIONS: The underlying factors of vaccine hesitancy are complex and context-specific, varying across time and socio-demographic variables. Vaccine hesitancy can also be influenced by other factors such as health inequalities, socioeconomic disadvantages, systemic racism, and level of exposure to misinformation online, with some factors being more dominant in certain countries than others. Therefore, strategies tailored to cultures and socio-psychological factors need to be developed to reduce vaccine hesitancy and aid informed decision-making.

Overview of Technologies Implemented During the First Wave of the COVID-19 Pandemic: Scoping Review.

BACKGROUND: Technologies have been extensively implemented to provide health care services for all types of clinical conditions during the COVID-19 pandemic. While several reviews have been conducted regarding technologies used during the COVID-19 pandemic, they were limited by focusing either on a specific technology (or features) or proposed rather than implemented technologies. OBJECTIVE: This review aims to provide an overview of technologies, as reported in the literature, implemented during the first wave of the COVID-19 pandemic. METHODS: We conducted a scoping review using PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-analyses) Extension for Scoping Reviews. Studies were retrieved by searching 8 electronic databases, checking the reference lists of included studies and relevant reviews (backward reference list checking), and checking studies that cited included studies (forward reference list checking). The search terms were chosen based on the target intervention (ie, technologies) and the target disease (ie, COVID-19). We included English publications that focused on technologies or digital tools implemented during the COVID-19 pandemic to provide health-related services regardless of target health condition, user, or setting. Two reviewers independently assessed the eligibility of studies and extracted data from eligible papers. We used a narrative approach to synthesize extracted data. RESULTS: Of 7374 retrieved papers, 126 were deemed eligible. Telemedicine was the most common type of technology (107/126, 84.9%) implemented in the first wave of the COVID-19 pandemic, and the most common mode of telemedicine was synchronous (100/108, 92.6%). The most common purpose of the technologies was providing consultation (75/126, 59.5%), followed by following up with patients (45/126, 35.7%), and monitoring their health status (22/126, 17.4%). Zoom (22/126, 17.5%) and WhatsApp (12/126, 9.5%) were the most commonly used videoconferencing and social media platforms, respectively. Both health care professionals and health consumers were the most common target users (103/126, 81.7%). The health condition most frequently targeted was COVID-19 (38/126, 30.2%), followed by any physical health conditions (21/126, 16.7%), and mental health conditions (13/126, 10.3%). Technologies were web-based in 84.1% of the studies (106/126). Technologies could be used through 11 modes, and the most common were mobile apps (86/126, 68.3%), desktop apps (73/126, 57.9%), telephone calls (49/126, 38.9%), and websites (45/126, 35.7%). CONCLUSIONS: Technologies played a crucial role in mitigating the challenges faced during the COVID-19 pandemic. We did not find papers describing the implementation of other technologies (eg, contact-tracing apps, drones, blockchain) during the first wave. Furthermore, technologies in this review were used for other purposes (eg, drugs and vaccines discovery, social distancing, and immunity passport). Future research on studies on these technologies and purposes is recommended, and further reviews are required to investigate technologies implemented in subsequent waves of the pandemic.

The Role of Neural Network for the Detection of Parkinson's Disease: A Scoping Review.

Background: Parkinson's Disease (PD) is a chronic neurodegenerative disorder that has been ranked second after Alzheimer's disease worldwide. Early diagnosis of PD is crucial to combat against PD to allow patients to deal with it properly. However, there is no medical test(s) available to diagnose PD conclusively. Therefore, computer-aided diagnosis (CAD) systems offered a better solution to make the necessary data-driven decisions and assist the physician. Numerous studies were conducted to propose CAD to diagnose PD in the early stages. No comprehensive reviews have been conducted to summarize the role of AI tools to combat PD. Objective: The study aimed to explore and summarize the applications of neural networks to diagnose PD. Methods: PRISMA Extension for Scoping Reviews (PRISMA-ScR) was followed to conduct this scoping review. To identify the relevant studies, both medical databases (e.g., PubMed) and technical databases (IEEE) were searched. Three reviewers carried out the study selection and extracted the data from the included studies independently. Then, the narrative approach was adopted to synthesis the extracted data. Results: Out of 1061 studies, 91 studies satisfied the eligibility criteria in this review. About half of the included studies have implemented artificial neural networks to diagnose PD. Numerous studies included focused on the freezing of gait (FoG). Biomedical voice and signal datasets were the most commonly used data types to develop and validate these models. However, MRI- and CT-scan images were also utilized in the included studies. Conclusion: Neural networks play an integral and substantial role in combating PD. Many possible applications of neural networks were identified in this review, however, most of them are limited up to research purposes.

Reprogramming of aerobic glycolysis in non-transformed mouse liver with pyruvate dehydrogenase complex deficiency.

The Pyruvate Dehydrogenase Complex (PDC), a key enzyme in glucose metabolism, catalyzes an irreversible oxidative decarboxylation reaction of pyruvate to acetyl-CoA, linking the cytosolic glycolytic pathway to mitochondrial tricarboxylic acid cycle and oxidative phosphorylation. Earlier we reported a down-regulation of several key hepatic lipogenic enzymes and their upstream regulators in liver-specific PDC-deficient mouse (L-PDCKO model by deleting the Pdha1 gene). In this study we investigated gene expression profiles of key glycolytic enzymes and other proteins that respond to various metabolic stresses in liver from L-PDCKO mice. Transcripts of several, such as hexokinase 2, phosphoglycerate kinase 1, pyruvate kinase muscle-type 2, and lactate dehydrogenase B as well as those for the nonglycolysis-related proteins, CD-36, C/EBP homologous protein, and peroxisome proliferator-activated receptor γ, were up-regulated in L-PDCKO liver whereas hypoxia-induced factor-1α, pyruvate dehydrogenase kinase 1 and Sirtuin 1 transcripts were down-regulated. The protein levels of pyruvate kinase muscle-type 2 and lactate dehydrogenase B were increased whereas that of lactate dehydrogenase A was decreased in PDC-deficient mouse liver. Analysis of endoplasmic reticulum and oxidative stress indicators suggests that the L-PDCKO liver showed evidence of the former but not the latter. These findings indicate that (i) liver-specific PDC deficiency is sufficient to induce "aerobic glycolysis characteristic" in mouse liver, and (ii) the mechanism(s) responsible for these changes appears distinct from that which induces the Warburg effect in some cancer cells.

Phenylbutyrate administration reduces changes in the cerebellar Purkinje cells population in PDC­deficient mice.

In humans, pyruvate dehydrogenase complex (PDC) deficiency impairs brain energy metabolism by reducing the availability of the functional acetyl­CoA pool. This "hypometabolic defect" results in congenital lactic acidosis and abnormalities of brain morphology and function, ranging from mild ataxia to profound psychomotor retardation. Our previous study showed reduction in total cell number and dendritic arbors in the cerebellar Purkinje cells in systemic PDC­deficient mice. Phenylbutyrate has been shown to increase PDC activity in cultured fibroblasts from PDC­deficient patients. Hence, we investigated the effects of postnatal (days 2­35) phenylbutyrate administration on the cerebellar Purkinje cell population in PDC­deficient female mice. Histological analyses of different regions of cerebellar cortex from the brain­specific PDC­deficient saline­injected mice revealed statistically significant reduction in the Purkinje cell density and increased cell size of the individual Purkinje cell soma compared to control PDC­normal, saline­injected group. Administration of phenylbutyrate to control mice did not cause significant changes in the Purkinje cell density and cell size in the studied regions. In contrast, administration of phenylbutyrate variably lessened the ill effects of PDC deficiency on Purkinje cell populations in different areas of the cerebellum. Our results lend further support for the possible use of phenylbutyrate as a potential treatment for PDC deficiency.

Lack of mitochondria-generated acetyl-CoA by pyruvate dehydrogenase complex downregulates gene expression in the hepatic de novo lipogenic pathway.

During the absorptive state, the liver stores excess glucose as glycogen and synthesizes fatty acids for triglyceride synthesis for export as very low density lipoproteins. For de novo synthesis of fatty acids from glucose, the mitochondrial pyruvate dehydrogenase complex (PDC) is the gatekeeper for the generation of acetyl-CoA from glucose-derived pyruvate. Here, we tested the hypothesis that limiting the supply of PDC-generated acetyl-CoA from glucose would have an impact on expression of key genes in the lipogenic pathway. In the present study, although the postnatal growth of liver-specific PDC-deficient (L-PDCKO) male mice was largely unaltered, the mice developed hyperinsulinemia with lower blood glucose levels in the fed state. Serum and liver lipid triglyceride and cholesterol levels remained unaltered in L-PDCKO mice. Expression of several key genes (ACL, ACC1) in the lipogenic pathway and their upstream regulators (LXR, SREBP1, ChREBP) as well as several genes in glucose metabolism (Pklr, G6pd2, Pck1) and fatty acid oxidation (FAT, Cpt1a) was downregulated in livers from L-PDCKO mice. Interestingly, there was concomitant upregulation of lipogenic genes in adipose tissue from L-PDCKO mice. Although, the total hepatic acetyl-CoA content remained unaltered in L-PDCKO mice, modified acetylation profiles of proteins in the nuclear compartment suggested an important role for PDC-generated acetyl-CoA in gene expression in de novo fatty acid synthesis in the liver. This finding has important implications for the regulation of hepatic lipid synthesis in pathological states.

Postnatal exposure to a high-carbohydrate diet interferes epigenetically with thyroid hormone receptor induction of the adult male rat skeletal muscle glucose transporter isoform 4 expression.

Early life nutritional intervention causes adult-onset insulin resistance and obesity in rats. Thyroid hormone receptor (TR), in turn, transcriptionally enhances skeletal muscle Glut4 expression. We tested the hypothesis that reduced circulating thyroid-stimulating hormone and T4 concentrations encountered in postnatal (PN4-PN24) high-carbohydrate (HC) milk formula-fed versus the mother-fed controls (MF) would epigenetically interfere with TR induction of adult (100 days) male rat skeletal muscle Glut4 expression, thereby providing a molecular mechanism mediating insulin resistance. We observed increased DNA methylation of the CpG island with enhanced recruitment of Dnmt3a, Dnmt3b and MeCP2 in the glut4 promoter region along with reduced acetylation of histone (H)2A.Z and H4 particularly at the H4.lysine (K)16 residue, which was predominantly mediated by histone deacetylase 4 (HDAC4). This was followed by enhanced recruitment of heterochromatin protein 1ß to the glut4 promoter with increased Suv39H1 methylase concentrations. These changes reduced TR binding of the T3 response element of the glut4 gene (TREs; -473 to -450 bp) detected qualitatively in vivo (electromobility shift assay) and quantified ex vivo (chromatin immunoprecipitation). In addition, the recruitment of steroid receptor coactivator and CREB-binding protein to the glut4 promoter-protein complex was reduced. Co-immunoprecipitation experiments confirmed the interaction between TR and CBP to be reduced and HDAC4 to be enhanced in HC versus MF groups. These molecular changes were associated with diminished skeletal muscle Glut4 mRNA and protein concentrations. We conclude that early postnatal exposure to HC diet epigenetically reduced TR induction of adult male skeletal muscle Glut4 expression, uncovering novel molecular mechanisms contributing to adult insulin resistance and obesity.

Featured Article: Beta cell specific pyruvate dehydrogenase alpha gene deletion results in a reduced islet number and ß-cell mass postnatally.

The ability of pancreatic ß-cells to undertake glucose-stimulated insulin secretion (GSIS) depends on the generation of adenosine triphosphate (ATP) within the mitochondria from pyruvate, a major rate-limiting enzyme being pyruvate dehydrogenase (PDH) complex (PDC). However, glucose metabolism also controls ß-cell mass. To examine the role of PDC in the regulation of pancreatic ß-cell development and maturation, we generated ß-cell-targeted PDHα subunit knock-out male mice (ß-PDHKO) and compared these with control males (ß-PDHCT) from birth until 6-8 weeks age. Pancreas morphology, transcription factor expression, pancreatic insulin content, and circulating glucose and insulin values were compared. Compared to ß-PDHCT male mice, ß-PDHKO animals had significantly reduced pancreatic insulin content from birth, a lower serum insulin content from day 15, and relative hyperglycemia from day 30. Isolated islets from ß-PDHKO mice demonstrated a reduced GSIS. The number of islets per pancreatic area, mean islet area, and the proportion of islet cells that were ß-cells were all reduced in ß-PDHKO animals. Similarly the number of insulin-immunopositive, extra-islet small endocrine cell clusters, a possible source of ß-cell progenitors, was lower in ß-PDHKO mice. Analysis of pancreatic expression of transcription factors responsible for ß-cell lineage commitment, proliferation, and maturation, Pdx1, Neurogenin3, and NeuroD1 showed that mRNA abundance was reduced in the ß-PDHKO. This demonstrates that PDC is not only required for insulin expression and glucose-stimulated secretion, but also directly influences ß-cell growth and maturity, and positions glucose metabolism as a direct regulator of ß-cell mass and plasticity.

Developmental programming in skeletal muscle in response to overnourishment in the immediate postnatal life in rats.

Overnourishment during the suckling period [small litter (SL)] results in the development of adult-onset obesity. To investigate the mechanisms that underlie the development of insulin resistance in the skeletal muscle of young and adult female SL rats, the litter size was reduced to 3 female pups/dam (SL) while the control litter had 12 pups/dam from the postnatal Day 3 until Day 21. Protein content, mRNA expression and methylation status of the promoter region of key components in the insulin signaling pathway were determined in the skeletal muscle of SL rats. Overnutrition during the suckling period resulted in increased body weight gains, hyperphagia and adult-onset obesity as well as increased levels of serum insulin, glucose and leptin in SL rats. No differences in the expression of total protein as well as tyrosine phosphorylation of insulin receptor ß and glucose transporter 4 (Glut4) were observed in skeletal muscle between two groups at both ages. A significant decrease of total insulin receptor substrate 1 (IRS-1) and an increase in serine phosphorylation of IRS-1 were observed in skeletal muscle from adult SL rats. Hypermethylation of specific cytidyl-3',5'phospho-guanylyl (CpG) dinucleotides in the proximal promoter region was observed for the Irs1 and Glut4 genes, which correlated with the reduction in Irs1 and Glut4 mRNA levels in skeletal muscle of adult SL rats. Our results suggest that epigenetic modifications of the key genes involved in the insulin signaling pathway in skeletal muscle could result in the development of insulin resistance in SL female rats.