Combined Effect of Maternal Separation and Early-Life Immune Activation on Brain and Behaviour of Rat Offspring.

Adversity during early life, a critical period for brain development, increases vulnerability and can have a lasting impact on the brain and behaviour of a child. However, the long-term effects of cumulative early-life stressors on brain and behaviour are not well known. We studied a 2-hit rat model of early-life adversity using maternal separation (MS) and immune activation (lipopolysaccharide (LPS)). Rat pups underwent MS for 15 (control) or 180 (MS) minutes per day from postnatal day (P)2-14 and were administered saline or LPS (intraperitoneal) on P3. Open-field (OFT) and object-place recognition tests were performed on rat offspring at P33-35 and P42-50, respectively. The pre-frontal cortex (PFC) and hippocampus were removed at the experimental endpoint (P52-55) for mRNA expression. MS induced anxiety-like behaviour in OFT in male and reduced locomotor activity in both male and female offspring. LPS induced a subtle decline in memory in the object-place recognition test in male offspring. MS increased glial fibrillary acidic protein (GFAP) and brain-derived neurotrophic factor expression in PFC and ionised calcium-binding adapter molecule-1 expression in male hippocampus. MS and LPS resulted in distinct behavioural phenotypes in a sex-specific manner. The combination of MS and LPS had a synergistic effect on the anxiety-like behaviour, locomotor activity, and GFAP mRNA expression outcomes.

The search for gastrointestinal inflammation in autism: a systematic review and meta-analysis of non-invasive gastrointestinal markers.

BACKGROUND: Gastrointestinal symptoms and inflammatory gastrointestinal diseases exist at higher rates in the autistic population. It is not clear however whether autism is associated with elevated gastrointestinal inflammation as studies examining non-invasive faecal biomarkers report conflicting findings. To understand the research landscape and identify gaps, we performed a systematic review and meta-analysis of studies measuring non-invasive markers of gastrointestinal inflammation in autistic and non-autistic samples. Our examination focused on faecal biomarkers as sampling is non-invasive and these markers are a direct reflection of inflammatory processes in the gastrointestinal tract. METHODS: We extracted data from case-control studies examining faecal markers of gastrointestinal inflammation. We searched PubMed, Embase, Cochrane CENTRAL, CINAHL, PsycINFO, Web of Science Core Collection and Epistemonikos and forward and backwards citations of included studies published up to April 14, 2023 (PROSPERO CRD42022369279). RESULTS: There were few studies examining faecal markers of gastrointestinal inflammation in the autistic population, and many established markers have not been studied. Meta-analyses of studies examining calprotectin (n = 9) and lactoferrin (n = 3) were carried out. A total of 508 autistic children and adolescents and 397 non-autistic children and adolescents were included in the meta-analysis of calprotectin studies which found no significant group differences (ROM: 1.30 [0.91, 1.86]). Estimated differences in calprotectin were lower in studies with siblings and studies which did not exclude non-autistic controls with gastrointestinal symptoms. A total of 139 autistic participants and 75 non-autistic controls were included in the meta-analysis of lactoferrin studies which found no significant group differences (ROM: 1.27 [0.79, 2.04]). LIMITATIONS: All studies included in this systematic review and meta-analysis examined children and adolescents. Many studies included non-autistic controls with gastrointestinal symptoms which limit the validity of their findings. The majority of studies of gastrointestinal inflammation focused on children under 12 with few studies including adolescent participants. Most studies that included participants aged four or under did not account for the impact of age on calprotectin levels. Future studies should screen for relevant confounders, include larger samples and explore gastrointestinal inflammation in autistic adolescents and adults. CONCLUSIONS: There is no evidence to suggest higher levels of gastrointestinal inflammation as measured by calprotectin and lactoferrin are present in autistic children and adolescents at the population level. Preliminary evidence suggests however that higher calprotectin levels may be present in a subset of autistic participants, who may be clinically characterised by more severe gastrointestinal symptoms and higher levels of autistic traits.

Targeted therapy, immunotherapy, and small molecules and peptidomimetics as emerging immunoregulatory agents for melanoma.

Primary cutaneous melanoma is the most lethal of all skin neoplasms and its incidence is increasing. Clinical management of advanced melanoma in the last decade has been revolutionised by the availability of immunotherapies and targeted therapies, used alone and in combination. This article summarizes advances in the treatment of late-stage melanoma including use of protein kinase inhibitors, antibody-based immune checkpoint inhibitors, adoptive immunotherapy, vaccines and more recently, small molecules and peptidomimetics as emerging immunoregulatory agents.

Complementary yet divergent effects of exercise and an exercise mimetic on microbiome in high-fat diet-induced obesity.

Exercise is beneficial for obesity, partially through increased mitochondrial activity and raised nicotinamide adenine dinucleotide (NAD), a coenzyme critical for mitochondrial function and metabolism. Recent work has shown that increasing the availability of NAD through pharmacological means improves metabolic health in rodent models of diet-induced obesity and that the effect of these supplements when administered orally may be modulated by the gut microbiome. The gut microbiome is altered by both diet and exercise and is thought to contribute to some aspects of high-fat diet-induced metabolic dysfunction. We examined the independent and combined effects of treadmill exercise and nicotinamide mononucleotide (NMN) supplementation on the gut microbiome of female C57Bl6/J mice chronically fed a high-fat diet. We showed that 8 wk of treadmill exercise, oral-administered NMN, or combined therapy exert unique effects on gut microbiome composition without changing bacterial species richness. Exercise and NMN exerted additive effects on microbiota composition, and NMN partially or fully restored predicted microbial functions, specifically carbohydrate and lipid metabolism, to control levels. Further research is warranted to better understand the mechanisms underpinning the interactions between exercise and oral NAD+ precursor supplementation on gut microbiome.NEW & NOTEWORTHY Exercise and NAD+ precursor supplementation exerted additive and independent effects on gut microbiota composition and inferred function in female mice with diet-induced obesity. Notably, combining exercise and oral nicotinamide mononucleotide supplementation restored inferred microbial functions to control levels, indicating that this combination may improve high-fat diet-induced alterations to microbial metabolism.

QDs-based fluorescent lateral flow assays for Point-of-care testing of insulin.

Point-of-care testing (POCT) can be performed near the site of the patient to achieve results in a few minutes. Different POCT devices are available in the market, such as microfluidic chips and paper-based lateral flow assays (LFAs). The paper-based LFAs have certain advantages, such as being cheap and disposable, able to detect a wide range of biomolecules, and the fluid flows through them via capillary action eliminating the need for external forces. The LFAs can be optimized for the sensitive and rapid detection of biomolecules. In this study, paper-based fluorescent LFAs platforms using aptamers as the biorecognition molecules were developed for the POCT of insulin. Various parameters were optimized such as concentrations of aptamers, the type of reporter molecules, the volume of sample, and the assay time to quantify insulin levels using a standard LFA reader. The fluorescent LFAs exhibited a linear detection range of 0.1-4 ng.mL-1 with a limit of detection (LOD) 0.1 ng.mL-1. The developed LFAs will help to achieve insulin measurement in a few minutes and will be easy to perform by end-users without the requirement of sophisticated instruments, laboratory set-up, and trained personnel. The developed device will be useful for the measurement of insulin levels in biological samples without the need for pretreatment, reducing the overall cost and time of testing. Moreover, the POCT device were fabricated using paper which is a low-cost (approximately AUD 2 per strip) option and is disposable.Clinical Relevance- POCT monitoring of insulin can facilitate both disease diagnosis and management. The developed LFAs have the capability of rapidly testing insulin concentration within several minutes. It will benefit both patients for at-home daily insulin monitoring and clinicians for hospital rapid insulin testing.

Parkinson's disease: From genetics to molecular dysfunction and targeted therapeutic approaches.

Parkinson's disease (PD) is the most common neurodegenerative movement disorder in the elderly. As the pathogenesis of PD is still not fully understood, medications with the capacity of halting the disease progression are currently unavailable. The discovery of genes that are causative for, or increase susceptibility to PD is pivotal for the development of novel therapeutic approaches, as they are critical for the onset of PD and the molecular pathways underlying its pathogenesis. By reviewing relevant data, we discuss causative genes, and those associated with PD susceptibility and quantitative traits. Through Gene Ontology database and STRING analysis, we emphasize the roles of inorganic cation transmembrane transport pathways and hypothalamic pituitary thyroid axis, in addition to the established roles of inflammation/oxidative stress and mitochondrial dysfunction in the pathogenesis of PD. It is hoped these insights 1) untangle the clinical complex presentations of PD, 2) reveal the interwoven molecular network leading to PD, and 3) identify critical molecular targets to facilitate novel PD drug discovery, with a view to providing improved consultation and personalized medicine for patients with PD in the future.

Obesogenic Diet Cycling Produces Graded Effects on Cognition and Microbiota Composition in Rats.

SCOPE: The effects of diet cycling on cognition and fecal microbiota are not well understood. METHOD AND RESULTS: Adult male Sprague-Dawley rats were cycled between a high-fat, high-sugar "cafeteria" diet (Caf) and regular chow. The impairment in place recognition memory produced by 16 days of Caf diet was reduced by switching to chow for 11 but not 4 days. Next, rats received 16 days of Caf diet in 2, 4, 8, or 16-day cycles, each separated by 4-day chow cycles. Place recognition memory declined from baseline in all groups and was impaired in the 16- versus 2-day group. Finally, rats received 24 days of Caf diet continuously or in 3-day cycles separated by 2- or 4-day chow cycles. Any Caf diet access impaired cognition and increased adiposity relative to controls, without altering hippocampal gene expression. Place recognition and adiposity were the strongest predictors of global microbiota composition. Overall, diets with higher Caf > chow ratios produced greater spatial memory impairments and larger shifts in gut microbiota species richness and beta diversity. CONCLUSION: Results suggest that diet-induced cognitive deficits worsen in proportion to unhealthy diet exposure, and that shifting to a healthy chow for at least a week is required for recovery under the conditions tested here.

Minocycline as Treatment for Psychiatric and Neurological Conditions: A Systematic Review and Meta-Analysis.

Minocycline has anti-inflammatory, antioxidant, and anti-apoptotic properties that explain the renewed interest in its use as an adjunctive treatment for psychiatric and neurological conditions. Following the completion of several new clinical trials using minocycline, we proposed an up-to-date systematic review and meta-analysis of the data available. The PICO (patient/population, intervention, comparison and outcomes) framework was used to search 5 databases aiming to identify randomized controlled trials that used minocycline as an adjunctive treatment for psychiatric and neurological conditions. Search results, data extraction, and risk of bias were performed by two independent authors for each publication. Quantitative meta-analysis was performed using RevMan software. Literature search and review resulted in 32 studies being included in this review: 10 in schizophrenia, 3 studies in depression, and 7 in stroke, with the benefit of minocycline being used in some of the core symptoms evaluated; 2 in bipolar disorder and 2 in substance use, without demonstrating a benefit for using minocycline; 1 in obsessive-compulsive disorder, 2 in brain and spinal injuries, 2 in amyotrophic lateral sclerosis, 1 in Alzheimer's disease, 1 in multiple systems atrophy, and 1 in pain, with mixes results. For most of the conditions included in this review the data is still limited and difficult to interpret, warranting more well-designed and powered studies. On the other hand, the studies available for schizophrenia seem to suggest an overall benefit favoring the use of minocycline as an adjunctive treatment.

Targeting negative energy balance with calorie restriction and mitochondrial uncoupling in db/db mice.

OBJECTIVE: Calorie restriction is a first-line treatment for overweight individuals with metabolic impairments. However, few patients can adhere to long-term calorie restriction. An alternative approach to calorie restriction that also causes negative energy balance is mitochondrial uncoupling, which decreases the amount of energy that can be extracted from food. Herein we compare the metabolic effects of calorie restriction with the mitochondrial uncoupler BAM15 in the db/db mouse model of severe hyperglycemia, obesity, hypertriglyceridemia, and fatty liver. METHODS: Male db/db mice were treated with ∼50% calorie restriction, BAM15 at two doses of 0.1% and 0.2% (w/w) admixed in diet, or 0.2% BAM15 with time-restricted feeding from 5 weeks of age. Mice were metabolically phenotyped over 4 weeks with assessment of key readouts including body weight, glucose tolerance, and liver steatosis. At termination, liver tissues were analysed by metabolomics and qPCR. RESULTS: Calorie restriction and high-dose 0.2% BAM15 decreased body weight to a similar extent, but mice treated with BAM15 had far better improvement in glucose control. High-dose BAM15 treatment completely normalized fasting glucose and glucose tolerance to levels similar to lean db/+ control mice. Low-dose 0.1% BAM15 did not affect body mass but partially improved glucose tolerance to a similar degree as 50% calorie restriction. Both calorie restriction and high-dose BAM15 significantly improved hyperglucagonemia and liver and serum triglyceride levels. Combining high-dose BAM15 with time-restricted feeding to match the time that calorie restricted mice were fed resulted in the best metabolic phenotype most similar to lean db/+ controls. BAM15-mediated improvements in glucose control were associated with decreased glucagon levels and decreased expression of enzymes involved in hepatic gluconeogenesis. CONCLUSIONS: BAM15 and calorie restriction treatments improved most metabolic disease phenotypes in db/db mice. However, mice fed BAM15 had superior effects on glucose control compared to the calorie restricted group that consumed half as much food. Submaximal dosing with BAM15 demonstrated that its beneficial effects on glucose control are independent of weight loss. These data highlight the potential for mitochondrial uncoupler pharmacotherapies in the treatment of metabolic disease.

The Benefits of Switching to a Healthy Diet on Metabolic, Cognitive, and Gut Microbiome Parameters Are Preserved in Adult Rat Offspring of Mothers Fed a High-Fat, High-Sugar Diet.

SCOPE: Maternal obesity increases the risk of health complications in children, highlighting the need for effective interventions. A rat model of maternal obesity to examine whether a diet switch intervention could reverse the adverse effects of an unhealthy postweaning diet is used. METHODS AND RESULTS: Male and female offspring born to dams fed standard chow or a high-fat, high-sugar "cafeteria" (Caf) diet are weaned onto chow or Caf diets until 22 weeks of age, when Caf-fed groups are switched to chow for 5 weeks. Adiposity, gut microbiota composition, and place recognition memory are assessed before and after the switch. Body weight and adiposity fall in switched groups but remain significantly higher than chow-fed controls. Nonetheless, the diet switch improves a deficit in place recognition memory observed in Caf-fed groups, increases gut microbiota species richness, and alters ß diversity. Modeling indicate that adiposity most strongly predicts gut microbiota composition before and after the switch. CONCLUSION: Maternal obesity does not alter the effects of switching diet on metabolic, microbial, or cognitive measures. Thus, a healthy diet intervention lead to major shifts in body weight, adiposity, place recognition memory, and gut microbiota composition, with beneficial effects preserved in offspring born to obese dams.

The effects of an obesogenic diet on behavior and cognition in zebrafish (Danio rerio): Trait average, variability, repeatability, and behavioral syndromes.

The obesity epidemic, largely driven by the accessibility of ultra-processed high-energy foods, is one of the most pressing public health challenges of the 21st century. Consequently, there is increasing concern about the impacts of diet-induced obesity on behavior and cognition. While research on this matter continues, to date, no study has explicitly investigated the effect of obesogenic diet on variance and covariance (correlation) in behavioral traits. Here, we examined how an obesogenic versus control diet impacts means and (co-)variances of traits associated with body condition, behavior, and cognition in a laboratory population of ~160 adult zebrafish (Danio rerio). Overall, an obesogenic diet increased variation in several zebrafish traits. Zebrafish on an obesogenic diet were significantly heavier and displayed higher body weight variability; fasting blood glucose levels were similar between control and treatment zebrafish. During behavioral assays, zebrafish on the obesogenic diet displayed more exploratory behavior and were less reactive to video stimuli with conspecifics during a personality test, but these significant differences were sex-specific. Zebrafish on an obesogenic diet also displayed repeatable responses in aversive learning tests whereas control zebrafish did not, suggesting an obesogenic diet resulted in more consistent, yet impaired, behavioral responses. Where behavioral syndromes existed (inter-class correlations between personality traits), they did not differ between obesogenic and control zebrafish groups. By integrating a multifaceted, holistic approach that incorporates components of (co-)variances, future studies will greatly benefit by quantifying neglected dimensions of obesogenic diets on behavioral changes.

The Role of the Microbiome in the Metabolic Health of People with Schizophrenia and Related Psychoses: Cross-Sectional and Pre-Post Lifestyle Intervention Analyses.

The microbiome has been implicated in the development of metabolic conditions which occur at high rates in people with schizophrenia and related psychoses. This exploratory proof-of-concept study aimed to: (i) characterize the gut microbiota in antipsychotic naïve or quasi-naïve people with first-episode psychosis, and people with established schizophrenia receiving clozapine therapy; (ii) test for microbiome changes following a lifestyle intervention which included diet and exercise education and physical activity. Participants were recruited from the Eastern Suburbs Mental Health Service, Sydney, Australia. Anthropometric, lifestyle and gut microbiota data were collected at baseline and following a 12-week lifestyle intervention. Stool samples underwent 16S rRNA sequencing to analyse microbiota diversity and composition. Seventeen people with established schizophrenia and five people with first-episode psychosis were recruited and matched with 22 age-sex, BMI and ethnicity matched controls from a concurrent study for baseline comparisons. There was no difference in α-diversity between groups at baseline, but microbial composition differed by 21 taxa between the established schizophrenia group and controls. In people with established illness pre-post comparison of α-diversity showed significant increases after the 12-week lifestyle intervention. This pilot study adds to the current literature that detail compositional differences in the gut microbiota of people with schizophrenia compared to those without mental illness and suggests that lifestyle interventions may increase gut microbial diversity in patients with established illness. These results show that microbiome studies are feasible in patients with established schizophrenia and larger studies are warranted to validate microbial signatures and understand the relevance of lifestyle change in the development of metabolic conditions in this population.

Intergenerational effects of overfeeding on aversive learning in zebrafish (Danio rerio).

The obesity epidemic is concerning as obesity appears to negatively impact cognition and behavior. Furthermore, some studies suggest that this negative effect could be carried across generations from both mothers and fathers although evidence is not consistent. Here, we attempt to address how obesogenic diets in the parental generation (F0) can impact offspring's cognition and anxiety intergenerationally (F1) in a zebrafish model. We compare both mean trait values and their variances. Using a multifactorial design, we created a total of four groups: F1T (treatment mothers × treatment fathers); F1M (treatment mothers × control fathers); F1P (treatment fathers × control mothers); and F1C (control mothers × control fathers, F1C); and subjected them to anxiety tank tests and aversive learning assays. When both parents were exposed, offspring (F1T) displayed the poorest aversive learning, while offspring that only had one parent exposed (F1P and F1M) learnt the aversive learning task the best. Zebrafish in all groups displayed no statistically significant differences in anxiety-associated behaviors. Males and females also performed similarly in both anxiety and aversive learning assays. While all F1 groups had similar levels of fasting blood glucose, variance in glucose levels were reduced in F1P and F1T indicating the importance of investigating heteroskedasticity between groups. Furthermore, anxiety behaviors of these two groups appeared to be less repeatable. To our knowledge, this is the first study to test the intergenerational effects of an obesogenic diet on zebrafish cognition. Our multifactorial design as well as repeated tests also allowed us to disentangle maternal and paternal effects (as well as combined effects) and accurately detect subtle information such as between-individual variation.

Dietary intake in children on the autism spectrum is altered and linked to differences in autistic traits and sensory processing styles.

Diets of children and adolescents on the autism spectrum often differ when compared to their non-autistic peers. Most dietary studies have been limited by small sample sizes and rarely assess the heterogeneity of autism. Addressing this gap, this study compared the anthropometrics, dietary composition, dietary quality, and food variety of 154 Australian children and adolescents on the spectrum and 213 non-autistic children (71 siblings and 142 unrelated controls). Beyond the case-control approach, within-group comparisons assessed the influence of autism clinical presentations and sensory processing styles on body mass index (BMI) and measures of dietary intake among those on the spectrum. In this word first study of diet that included between-group comparisons with non-autistic peers (siblings and an unrelated comparison group) and within-autism group comparisons, we found that children on the spectrum consumed limited variety and lower quality of food and non-autistic siblings also ate comparably higher levels of energy-dense, nutrient poor food, and less diary. This may be due to autistic traits influencing family's diets or shared sensory sensitivities driving dietary intake. Within the autism group, higher autistic traits were associated with lower BMIs and a specific dietary pattern higher in simple carbohydrates and lower in unprocessed protein. Contrastingly, greater sensitivity to sensory stimuli was associated with a healthier diet. Increased age was linked to more varied diets but also diets higher in saturated fats and energy-dense, nutrient poor foods. Overall, this research highlights that potential mediators of dietary intake, such as familial influences, autistic traits, sensory processing styles, age and sex, need to be considered when assessing diet in the autistic population. LAY SUMMARY: In this study of dietary differences linked to autism, children, and teenagers on the spectrum ate fewer different foods and were less likely to eat recommended amounts of fruits and vegetables when compared to non-autistic siblings and unrelated children and teenagers. There were also family differences, in that those on the spectrum and their siblings ate more unhealthy foods and less dairy. Among those on the spectrum, dietary differences were linked to age, sex, autistic traits and sensory processing styles.

Concurrent betaine administration enhances exercise-induced improvements to glucose handling in obese mice.

BACKGROUND AND AIMS: Betaine supplementation has been shown to enhance hepatic lipid metabolism in obese mice and improve exercise performance in healthy populations. We examined effects of betaine supplementation, alone or in combination with treadmill exercise, on the metabolic consequences of high fat diet (HFD)-induced obesity in mice. METHODS AND RESULTS: Male C57BL/6 J mice were fed chow or HFD. After 15 weeks, HFD mice were split into: HFD, HFD with betaine (1.5% w/v), HFD with treadmill exercise, and HFD with both betaine and exercise (15 m/min for 45min, 6 days/week; n = 12/group) for 10 weeks. Compared to HFD mice, body weight was significantly reduced in exercise and exercise-betaine mice, but not in mice given betaine alone. Similarly, adiposity was reduced by exercise but not by betaine alone. HFD-induced glucose intolerance was slightly improved by exercise, but not with betaine alone. Significantly greater benefits were observed in exercise-betaine mice, compared to exercise alone, such that GTT-outcomes were similar to controls. This was associated with reduced insulin levels during ipGTT, suggesting enhanced insulin sensitivity. Modest benefits were observed in fatty acid metabolism genes in skeletal muscle, whilst limited effects were observed in the liver. HFD-induced increases in hepatic Mpc1 (mitochondrial pyruvate carrier 1) were normalized by all treatments, suggesting potential links to altered glucose metabolism. CONCLUSIONS: Our data show that drinking 1.5% betaine was sufficient to augment metabolic benefits of exercise in obese mice. These processes appear to be facilitated by altered glucose metabolism, with limited effects on hepatic lipid metabolism.

Ameliorating high-fat diet-induced sperm and testicular oxidative damage by micronutrient-based antioxidant intervention in rats.

PURPOSE: Emerging evidence from rodent studies suggests that high-fat-diet (HFD)-induced obesity is characterized by increased oxidative damage in sperm and testis. However, interventions using micronutrient supplementation to mitigate oxidative damage in obesity have not been extensively studied. This study aimed to investigate the effect of an antioxidant-based micronutrient supplement (added folate, vitamin B6, choline, betaine, and zinc) on sperm and testicular oxidative damage in HFD-fed male Sprague Dawley rats. METHODS: Rats (3-weeks-old, 12/group) were weaned onto control (C) or HFD (H) or these diets with micronutrient supplement (CS; HS); sperm and testis were harvested at 30.5 weeks. To assess oxidative stress and antioxidant capacity in testis, levels of malondialdehyde (MDA), glutathione (GSH), folate and susceptibility index (SI) of pro-oxidative damage, mRNA expression of Nrf2, NFκB-p65, IL-6, IL-10 and TNF-α, in addition to superoxide-dismutase (SOD), catalase and glutathione-peroxidase (GPx) activities were measured. 8-hydroxy-2-deoxyguanosine (8-OHdG) were assessed in both sperm and testis. RESULTS: HFD-fed rats had significantly increased 8-OHdG content in sperm and testis, increased testicular SI, decreased testicular weight, SOD and GPx activity compared to control. Strikingly, supplementation of HFD appeared to significantly reduce 8-OHdG in sperm and testis (22% and 24.3%, respectively), reduce testicular SI and MDA content (28% and 40%, respectively), increase testicular weight (24%), SOD and GPX activity (30% and 70%, respectively) and GSH content (19%). Moreover, supplementation had significant impact to increase testicular folate content regardless of diet. Furthermore, an overall effect of supplementation to increase testicular mRNA expression of Nrf2 was observed across groups. Interestingly, testicular SI was positively correlated with sperm and testicular 8-OHdG and MDA content, suggesting a critical role of testicular antioxidant activity to combat oxidative damage in sperm and testis. CONCLUSION: Our findings suggest that antioxidant-based micronutrient supplement has the potential to interrupt HFD-induced sperm and testicular oxidative damage by improving testicular antioxidant capacity.

Ancestral dietary change alters the development of Drosophila larvae through MAPK signalling.

Studies in a broad range of animal species have revealed phenotypes that are caused by ancestral life experiences, including stress and diet. Ancestral dietary macronutrient composition and quantity (over- and under-nutrition) have been shown to alter descendent growth, metabolism and behaviour. Molecules have been identified in gametes that are changed by ancestral diet and are required for transgenerational effects. However, there is less understanding of the developmental pathways altered by inherited molecules during the period between fertilization and adulthood. To investigate this non-genetic inheritance, we exposed great grand-parental and grand-parental generations to defined protein to carbohydrate (P:C) dietary ratios. Descendent developmental timing was consistently faster in the period between the embryonic and pupal stages when ancestors had a higher P:C ratio diet. Transcriptional analysis revealed extensive and long-lasting changes to the MAPK signalling pathway, which controls growth rate through the regulation of ribosomal RNA transcription. Pharmacological inhibition of both MAPK and rRNA pathways recapitulated the ancestral diet-induced developmental changes. This work provides insight into non-genetic inheritance between fertilization and adulthood.

Acetyl-CoA metabolism drives epigenome change and contributes to carcinogenesis risk in fatty liver disease.

BACKGROUND: The incidence of non-alcoholic fatty liver disease (NAFLD)-associated hepatocellular carcinoma (HCC) is increasing worldwide, but the steps in precancerous hepatocytes which lead to HCC driver mutations are not well understood. Here we provide evidence that metabolically driven histone hyperacetylation in steatotic hepatocytes can increase DNA damage to initiate carcinogenesis. METHODS: Global epigenetic state was assessed in liver samples from high-fat diet or high-fructose diet rodent models, as well as in cultured immortalized human hepatocytes (IHH cells). The mechanisms linking steatosis, histone acetylation and DNA damage were investigated by computational metabolic modelling as well as through manipulation of IHH cells with metabolic and epigenetic inhibitors. Chromatin immunoprecipitation and next-generation sequencing (ChIP-seq) and transcriptome (RNA-seq) analyses were performed on IHH cells. Mutation locations and patterns were compared between the IHH cell model and genome sequence data from preneoplastic fatty liver samples from patients with alcohol-related liver disease and NAFLD. RESULTS: Genome-wide histone acetylation was increased in steatotic livers of rodents fed high-fructose or high-fat diet. In vitro, steatosis relaxed chromatin and increased DNA damage marker γH2AX, which was reversed by inhibiting acetyl-CoA production. Steatosis-associated acetylation and γH2AX were enriched at gene clusters in telomere-proximal regions which contained HCC tumour suppressors in hepatocytes and human fatty livers. Regions of metabolically driven epigenetic change also had increased levels of DNA mutation in non-cancerous tissue from NAFLD and alcohol-related liver disease patients. Finally, genome-scale network modelling indicated that redox balance could be a key contributor to this mechanism. CONCLUSIONS: Abnormal histone hyperacetylation facilitates DNA damage in steatotic hepatocytes and is a potential initiating event in hepatocellular carcinogenesis.