Unlocking hidden potential: advancements, approaches, and obstacles in repurposing drugs for cancer therapy.

High rates of failure, exorbitant costs, and the sluggish pace of new drug discovery and development have led to a growing interest in repurposing "old" drugs to treat both common and rare diseases, particularly cancer. Cancer, a complex and heterogeneous disease, often necessitates a combination of different treatment modalities to achieve optimal outcomes. The intrinsic polygenicity of cancer, intricate biological signalling networks, and feedback loops make the inhibition of a single target frequently insufficient for achieving the desired therapeutic impact. As a result, addressing these complex or "smart" malignancies demands equally sophisticated treatment strategies. Combinatory treatments that target the multifaceted oncogenic signalling network hold immense promise. Repurposed drugs offer a potential solution to this challenge, harnessing known compounds for new indications. By avoiding the prohibitive costs and long development timelines associated with novel cancer drugs, this approach holds the potential to usher in more effective, efficient, and cost-effective cancer treatments. The pursuit of combinatory therapies through drug repurposing may hold the key to achieving superior outcomes for cancer patients. However, drug repurposing faces significant commercial, technological and regulatory challenges that need to be addressed. This review explores the diverse approaches employed in drug repurposing, delves into the challenges faced by the drug repurposing community, and presents innovative solutions to overcome these obstacles. By emphasising the significance of combinatory treatments within the context of drug repurposing, we aim to unlock the full potential of this approach for enhancing cancer therapy. The positive aspects of drug repurposing in oncology are underscored here; encompassing personalized treatment, accelerated development, market opportunities for shelved drugs, cancer prevention, expanded patient reach, improved patient access, multi-partner collaborations, increased likelihood of approval, reduced costs, and enhanced combination therapy.

Preterm-born individuals: a vulnerable population at risk of cardiovascular morbidity and mortality during thermal extremes?

NEW FINDINGS: What is the topic of this review? Thermal extremes disproportionately affect populations with cardiovascular conditions. Preterm birth, across all gestational age ranges below 37 weeks, has been identified as a non-modifiable risk factor for cardiovascular disease. The hypothesis is presented that individuals born preterm are at an increased risk of cardiovascular morbidity and mortality during thermal extremes. What advances does it highlight? Cardiovascular stress tests performed in preterm-born populations, from infancy through adulthood, highlight a progression of cardiovascular dysfunction accelerating through adolescence and adulthood. This dysfunction has many similarities with populations known to be at risk in thermal extremes. ABSTRACT: Preterm-born individuals are a uniquely vulnerable population. Preterm exposure to the extrauterine environment and the (mal)adaptations that occur during the transitional period can result in alterations to their macro- and micro-physiological state. The physiological adaptations that increase survival in the short term may place those born preterm on a trajectory of lifelong dysfunction and later-life decompensation. Cardiovascular compensation in children and adolescents, which masks this trajectory of dysfunction, is overcome under stress, such that the functional cardiovascular capacity is reduced and recovery impaired following physiological stress. This has implications for their response to thermal stress. As the Anthropocene introduces greater changes in our environment, thermal extremes will impact vulnerable populations as yet unidentified in the climate change context. Here, we present the hypothesis that individuals born preterm are a vulnerable population at an increased risk of cardiovascular morbidity and mortality during thermal extremes.

A novel whole-body thermal stress test for monitoring cardiovascular responses in guinea pigs.

Cardiovascular disease is a leading cause of morbidity and mortality worldwide. Stress tests are frequently employed to expose early signs of cardiovascular dysfunction or disease and can be employed, for example, in the context of preterm birth. We aimed to establish a safe and effective thermal stress test to examine cardiovascular function. Guinea pigs were anaesthetized using a 0.8% isoflurane, 70% N2O mix. ECG, non-invasive blood pressure, laser Doppler flowmetry, respiratory rate, and an array of skin and rectal thermistors were applied. A physiologically relevant heating and a cooling thermal stress test was developed. Upper and lower thermal limits for core body temperature were set at 41.5 OC and 34 OC, for the safe recovery of animals. This protocol therefore presents a viable thermal stress test for use in guinea pig models of health and disease that facilitates exploration of whole-system cardiovascular function.

Cancer Metastasis and Treatment Resistance: Mechanistic Insights and Therapeutic Targeting of Cancer Stem Cells and the Tumor Microenvironment.

Cancer metastasis and treatment resistance are the main causes of treatment failure and cancer-related deaths. Their underlying mechanisms remain to be fully elucidated and have been attributed to the presence of cancer stem cells (CSCs)-a small population of highly tumorigenic cancer cells with pluripotency and self-renewal properties, at the apex of a cellular hierarchy. CSCs drive metastasis and treatment resistance and are sustained by a dynamic tumor microenvironment (TME). Numerous pathways mediate communication between CSCs and/or the surrounding TME. These include a paracrine renin-angiotensin system and its convergent signaling pathways, the immune system, and other signaling pathways including the Notch, Wnt/ß-catenin, and Sonic Hedgehog pathways. Appreciation of the mechanisms underlying metastasis and treatment resistance, and the pathways that regulate CSCs and the TME, is essential for developing a durable treatment for cancer. Pre-clinical and clinical studies exploring single-point modulation of the pathways regulating CSCs and the surrounding TME, have yielded partial and sometimes negative results. This may be explained by the presence of uninhibited alternative signaling pathways. An effective treatment of cancer may require a multi-target strategy with multi-step inhibition of signaling pathways that regulate CSCs and the TME, in lieu of the long-standing pursuit of a 'silver-bullet' single-target approach.

Maternal Fructose Intake, Programmed Mitochondrial Function and Predisposition to Adult Disease.

Fructose consumption is now recognised as a major risk factor in the development of metabolic diseases, such as hyperlipidaemia, diabetes, non-alcoholic fatty liver disease and obesity. In addition to environmental, social, and genetic factors, an unfavourable intrauterine environment is now also recognised as an important factor in the progression of, or susceptibility to, metabolic disease during adulthood. Developmental trajectory in the short term, in response to nutrient restriction or excessive nutrient availability, may promote adaptation that serves to maintain organ functionality necessary for immediate survival and foetal development. Consequently, this may lead to decreased function of organ systems when presented with an unfavourable neonatal, adolescent and/or adult nutritional environment. These early events may exacerbate susceptibility to later-life disease since sub-optimal maternal nutrition increases the risk of non-communicable diseases (NCDs) in future generations. Earlier dietary interventions, implemented in pregnant mothers or those considering pregnancy, may have added benefit. Although, the mechanisms by which maternal diets high in fructose and the vertical transmission of maternal metabolic phenotype may lead to the predisposition to adult disease are poorly understood. In this review, we will discuss the potential contribution of excessive fructose intake during pregnancy and how this may lead to developmental reprogramming of mitochondrial function and predisposition to metabolic disease in offspring.

Development and the art of nutritional maintenance.

Development from early conceptus to a complex, multi-cellular organism is a highly ordered process that is dependent on an adequate supply of nutrients. During this process, the pattern of organ growth is robust, driven by a genetic blueprint and matched to anticipated body mass with high precision and with built-in physiological reserve capacity. This apparent canalisation of the developmental process is particularly sensitive to variation in environmental stimuli, such as inappropriate drug or hormone exposure, or pattern of nutrient delivery. Significant variation in any of these factors can profoundly affect fetal and neonatal growth patterns, with later detriment for physiological function and/or reserve capacity of the resultant adult, with potential health impact. This paradigm shift in science has become known as the Developmental Origins of Health and Disease (DOHaD). Over the last 30 years, many animal and clinical studies have vastly expanded our fundamental knowledge of developmental biology, particularly in the context of later effects on health. In this horizons article, we discuss DOHaD through the lens of nutritional quality (e.g. micronutrient, amino acid, NSP intake). The concept of 'Quality' was considered undefinable by Robert Persig in his book, 'Zen and the Art of Motorcycle Maintenance'. Here, development and the art of nutritional maintenance will define quality in terms of the pattern of nutrient intake, the quality of development and how each interact to influence later health outcomes.

Effects of Freshly Irradiated vs Irradiated and Stored Red Blood Cell Transfusion on Cerebral Oxygenation in Preterm Infants: A Randomized Clinical Trial.

Importance: Gamma irradiation of leukoreduced red blood cells (RBCs) prevents transfusion-associated graft-vs-host disease but also exacerbates storage lesion formation in RBCs. It is unknown whether freshly irradiated RBCs are more efficacious than irradiated and stored RBCs in preterm infants with high transfusion requirements. Objective: To examine whether transfusion of freshly irradiated vs irradiated and stored RBC components improves cerebral oxygen delivery in preterm infants with anemia. Design, Setting, and Participants: This single-center, double-blinded, proof-of-concept randomized clinical trial was conducted at the neonatal intensive care unit of Wellington Regional Hospital in Wellington, New Zealand, between December 1, 2017, and November 30, 2018. Participants were preterm infants (<34 weeks' gestation at birth) who were at least 14 days of age and had anemia. Participants underwent nonurgent transfusions, and these episodes were randomized to the intervention group (in which the infants received a transfusion of RBCs that were freshly irradiated on the day of transfusion) or control group (in which the infants received a transfusion of RBCs that were irradiated and stored for up to 14 days). Data were analyzed using the evaluable population approach. Intervention: Transfusion of freshly irradiated RBCs. Main Outcomes and Measures: The prespecified primary outcome was the change in cerebral regional oxygen saturation (crSO2) from baseline (immediately before) to immediately after the transfusion. The prespecified secondary outcomes were the change in cerebral fractional tissue oxygen extraction (cFTOE) at different time points (immediately after, 24 hours after, and 120 hours or 5 days after transfusion). Outcomes were measured by blinded clinicians using near-infrared spectroscopy. A covariate-adjusted linear mixed model was used to quantify mean treatment effects and account for multiple transfusions in some infants. Results: A total of 42 infants (mean [SD] gestational age, 26 [10] weeks and 3 days; 29 [69%] boys) were enrolled in the trial and underwent 64 transfusion episodes, which were randomized to the intervention (n = 31) or control (n = 33) group. Compared with infants in the control group, those in the intervention group showed a covariate-adjusted mean increase in crSO2 (2.0 percentage points; 95% CI, 1.2-2.8 percentage points) and a mean decrease in cFTOE (0.02; 95% CI, 0.01-0.04) immediately after transfusion. These differences were sustained up to 120 hours or 5 days after transfusion. There were negligible mean changes in crSO2 or cFTOE in infants in the control group at any of the follow-up time points. Conclusions and Relevance: Results of this trial showed that transfusion of freshly irradiated RBCs conferred a small advantage in cerebral oxygenation for at least 5 days after transfusion compared with transfusion of irradiated and stored RBC components. On-demand irradiation of RBC components may be considered to optimize oxygen delivery in the recipient, but this physiological finding requires further research. Trial Registration: ANZCTR Identifier: ACTRN12617001581358.

Maternal Fructose Intake Causes Developmental Reprogramming of Hepatic Mitochondrial Catalytic Activity and Lipid Metabolism in Weanling and Young Adult Offspring.

Excess dietary fructose is a major public health concern, yet little is known about its influence on offspring development and later-life disease when consumed in excess during pregnancy. To determine whether increased maternal fructose intake could have long-term consequences on offspring health, we investigated the effects of 10% w/v fructose water intake during preconception and pregnancy in guinea pigs. Female Dunkin Hartley guinea pigs were fed a control diet (CD) or fructose diet (FD; providing 16% of total daily caloric intake) ad libitum 60 days prior to mating and throughout gestation. Dietary interventions ceased at day of delivery. Offspring were culled at day 21 (D21) (weaning) and at 4 months (4 M) (young adult). Fetal exposure to excess maternal fructose intake significantly increased male and female triglycerides at D21 and 4 M and circulating palmitoleic acid and total omega-7 through day 0 (D0) to 4 M. Proteomic and functional analysis of significantly differentially expressed proteins revealed that FD offspring (D21 and 4 M) had significantly increased mitochondrial metabolic activities of ß-oxidation, electron transport chain (ETC) and oxidative phosphorylation and reactive oxygen species production compared to the CD offspring. Western blotting analysis of both FD offspring validated the increased protein abundances of mitochondrial ETC complex II and IV, SREBP-1c and FAS, whereas VDAC1 expression was higher at D21 but lower at 4 M. We provide evidence demonstrating offspring programmed hepatic mitochondrial metabolism and de novo lipogenesis following excess maternal fructose exposure. These underlying asymptomatic programmed pathways may lead to a predisposition to metabolic dysfunction later in life.

Utility of the Cerebral Organoid Glioma 'GLICO' Model for Screening Applications.

Glioblastoma, a grade IV astrocytoma, is regarded as the most aggressive primary brain tumour with an overall median survival of 16.0 months following the standard treatment regimen of surgical resection, followed by radiotherapy and chemotherapy with temozolomide. Despite such intensive treatment, the tumour almost invariably recurs. This poor prognosis has most commonly been attributed to the initiation, propagation, and differentiation of cancer stem cells. Despite the unprecedented advances in biomedical research over the last decade, the current in vitro models are limited at preserving the inter- and intra-tumoural heterogeneity of primary tumours. The ability to understand and manipulate complex cancers such as glioblastoma requires disease models to be clinically and translationally relevant and encompass the cellular heterogeneity of such cancers. Therefore, brain cancer research models need to aim to recapitulate glioblastoma stem cell function, whilst remaining amenable for analysis. Fortunately, the recent development of 3D cultures has overcome some of these challenges, and cerebral organoids are emerging as cutting-edge tools in glioblastoma research. The opportunity to generate cerebral organoids via induced pluripotent stem cells, and to perform co-cultures with patient-derived cancer stem cells (GLICO model), has enabled the analysis of cancer development in a context that better mimics brain tissue architecture. In this article, we review the recent literature on the use of patient-derived glioblastoma organoid models and their applicability for drug screening, as well as provide a potential workflow for screening using the GLICO model. The proposed workflow is practical for use in most laboratories with accessible materials and equipment, a good first pass, and no animal work required. This workflow is also amenable for analysis, with separate measures of invasion, growth, and viability.

Differential effects of four intramuscular sedatives on cardiorespiratory stability in juvenile guinea pigs (Cavia porcellus).

BACKGROUND: Non-invasive physiological monitoring can induce stress in laboratory animals. Sedation reduces the level of restraint required, thereby improving the validity of physiological signals measured. However, sedatives may alter physiological equilibrium introducing unintended bias and/or, masking the experimental outcomes of interest. We aimed to investigate the cardiorespiratory effects of four short-acting sedatives in juvenile guinea pigs. METHOD: 12 healthy, 38 (26-46) day-old Dunkin Hartley guinea pigs were included in this blinded, randomised, crossover design study. Animals were sedated by intramuscular injection using pre-established minimum effective doses of either alfaxalone (5 mg/kg), diazepam (5 mg/kg), ketamine (30 mg/kg), or midazolam (2 mg/kg) administered in random order with a minimum washout period of 48 hours between agents. Sedative depth, a composite score comprised of five assessment criteria, was observed every 5-min from dosing until arousal. Physiological monitoring of cardiorespiratory status included measures of heart rate, blood pressure, respiratory rate, and peripheral microvascular perfusion. RESULTS: Ketamine and alfaxalone were most effective in inducing stable sedation suitable for physiological monitoring, and diazepam less-so. Midazolam was unsuitable due to excessive hypersensitivity. All sedatives significantly increased heart rate above non-sedated control rates (P<0.0001), without altering blood pressure or microvascular perfusion. Alfaxalone and ketamine reduced respiratory rate relative to their control condition (P<0.0001, P = 0.05, respectively), but within normative ranges. CONCLUSION: Ketamine and alfaxalone are the most effective sedatives for inducing short duration, stable sedation with minimal cardiorespiratory depression in guinea pigs, while diazepam is less-so. However, alfaxalone is the most appropriate sedative for longitudinal studies requiring multiple physiological timepoints.

Nitrous oxide improves cardiovascular, respiratory, and thermal stability during prolonged isoflurane anesthesia in juvenile guinea pigs.

Anesthesia is frequently used to facilitate physiological monitoring during interventional animal studies. However, its use may induce cardiovascular (central and peripheral), respiratory, and thermoregulatory depression, confounding results in anesthetized animals. Despite the wide utility of guinea pigs as a translational platform, anesthetic protocols remain unstandardized for extended physiological studies in this species. Therefore, optimizing an anesthetic protocol that balances stable anesthesia with intact cardiorespiratory and metabolic function is crucial. To achieve this, 12 age and sex-matched juvenile Dunkin Hartley guinea pigs underwent extended anesthesia (≤150 min) with either (a) isoflurane (ISO: 1.5%), or (b) isoflurane + N2 O (ISO+ N2 O: 0.8% +70%), in this randomized cross-over designed study. Cardiovascular (HR, SBP, peripheral microvascular blood flow), respiratory (respiratory rate, SpO2 ), and thermal (Tre and Tsk ) measures were recorded continuously throughout anesthesia. Blood gas measures pre- and post- anesthesia were performed. Incorporation of 70% N2 O allowed for significant reductions in isoflurane (to 0.8%) while maintaining an effective anesthetic depth for prolonged noninvasive physiological examination in guinea pigs. ISO+N2 O maintained heart rate, peripheral blood flow, respiratory rate, and thermoregulatory function at levels closest to those of conscious animals, especially in females; however, it did not fully rescue anesthesia-induced hypotension. These results suggest that for studies requiring prolonged physiological examination (≤150 min) in guinea pigs, 0.8% isoflurane with a 70% N2 O adjuvant provides adequate anesthesia, while minimizing associated cardiorespiratory depression. The preservation of cardiorespiratory status is most marked throughout the first hour of anesthesia.

Fructose Consumption During Pregnancy Influences Milk Lipid Composition and Offspring Lipid Profiles in Guinea Pigs.

Excess dietary fructose is a major public health concern (1-4). Evidence shows increased fructose intake can cause insulin resistance, hepatic de novo lipogenesis, hypertriglyceridemia, obesity and non-alcoholic fatty liver disease (NAFLD) (5-9). However, little is known about the effects of fructose during pregnancy and its influence on offspring development and predisposition to later-life disease. To determine whether moderately increased maternal fructose intake could have health consequences on offspring, we have investigated the effects of 10% w/v fructose water intake during preconception and pregnancy. Female Dunkin Hartley guinea pigs were fed a control diet (CD) or fructose diet (FD;10% kcal from fructose) ad-libitum 60 days prior to mating and throughout gestation. Offspring were culled at weaning, day 21 (d21). Compared to CD dams, FD dams had altered glucose metabolism and increased milk free fatty acid content. Matsuda-DeFronzo insulin sensitivity index (M-ISI) from OGTT plasma showed no significant difference in whole-body insulin sensitivity between FD and CD dams 60 days post-dietary intervention and during midgestation. Fetal exposure to increased maternal fructose resulted in offspring with significantly altered serum free fatty acids at days 0, 7, 14, and 21 [including pentadecanoic acid (15:0), dma16:0, margaric acid (17:0) palmitoleic acid, total omega-7 and total saturates], increased levels of uric acid and triglycerides were also observed at d21. We have demonstrated that increased fructose intake during pregnancy can cause significant changes in maternal metabolic function and milk composition, which alters offspring metabolism. Taken together, these changes in pregnancy outcomes and feto-maternal condition may underlie their offspring's predisposition to metabolic dysfunction during later-life.

Methamphetamine administration increases hepatic CYP1A2 but not CYP3A activity in female guinea pigs.

Methamphetamine use has increased over the past decade and the first use of methamphetamine is most often when women are of reproductive age. Methamphetamine accumulates in the liver; however, little is known about the effect of methamphetamine use on hepatic drug metabolism. Methamphetamine was administered on 3 occassions to female Dunkin Hartley guinea pigs of reproductive age, mimicking recreational drug use. Low doses of test drugs caffeine and midazolam were administered after the third dose of methamphetamine to assess the functional activity of cytochrome P450 1A2 and 3A, respectively. Real-time quantitative polymerase chain reaction was used to quantify the mRNA expression of factors involved in glucocorticoid signalling, inflammation, oxidative stress and drug transporters. This study showed that methamphetamine administration decreased hepatic CYP1A2 mRNA expression, but increased CYP1A2 enzyme activity. Methamphetamine had no effect on CYP3A enzyme activity. In addition, we found that methamphetamine may also result in changes in glucocorticoid bioavailability, as we found a decrease in 11ß-hydroxysteroid dehydrogenase 1 mRNA expression, which converts inactive cortisone into active cortisol. This study has shown that methamphetamine administration has the potential to alter drug metabolism via the CYP1A2 metabolic pathway in female guinea pigs. This may have clinical implications for drug dosing in female methamphetamine users of reproductive age.

Cyclic glycine-proline normalizes systolic blood pressure in high-fat diet-induced obese male rats.

BACKGROUND AND AIMS: Insulin-like growth factor (IGF)-1 deficiency is associated with a range of metabolic disorders. Cyclic glycine-proline (cGP) is a natural nutrient and regulates the amount of active IGF-1 in plasma. Plasma cGP decreases in hypertensive women whereas increases in obese women, suggesting its involvement in cardio-metabolic function. We therefore examined the effects of cGP on metabolic profiles and blood pressure in high-fat diet (HFD)-induced obese male rats. METHODS: Male rats were fed either a HFD or a standard chow diet (STD) ad-libitum from 3 to 15 weeks of age. Rats were administered either saline or cGP from 11 to 15 weeks of age. At 14 weeks of age, systolic-blood pressure (SBP) was measured by tail-cuff plethysmography and body composition quantified by DEXA. Blood and retroperitoneal fat tissues were collected. Plasma concentrations of insulin, IGF-1, IGF binding protein (IGFBP)-3 and cGP were evaluated using ELISA and HPLC-MS respectively. RESULTS: Compared to STD, HFD feeding increased SBP, total fat mass and fat/lean ratio, retroperitoneal fat weight, fasting plasma insulin and cGP concentrations whereas decreased plasma IGF-1 and IGFBP-3 concentrations. Administration of cGP reduced SBP and retroperitoneal fat weight, but had no effect on body composition and plasma insulin concentrations. CONCLUSION: HFD-associated decreases in IGFBP-3 and increases in cGP represent an autocrine response to normalize IGF-1 function through improving the amount of bioavailable IGF-1 in the circulation of obese male rats. The beneficial effects of cGP on SBP and retroperitoneal fat mass may suggest a therapeutic potential for cGP in HFD-associated cardio-metabolic complications.

Dietary nitrate supplementation enhances cerebrovascular CO2 reactivity in a sex-specific manner.

Insufficient nitric oxide (NO) bioavailability plays an important role in endothelial dysfunction, and increased NO has the potential to enhance cerebral blood flow (CBF). Dietary supplementation with sodium nitrate, a precursor of NO, could improve cerebrovascular function, but this has not been investigated. In 17 individuals, we examined the effects of a 7-day supplementation of dietary nitrate (0.1 mmol·kg-1·day -1) on cerebrovascular function using a randomized, single-blinded placebo-controlled crossover design. We hypothesized that 7-day dietary nitrate supplementation increases CBF response to CO2 (cerebrovascular CO2 reactivity) and cerebral autoregulation (CA). We assessed middle cerebral artery blood velocity (MCAv) and blood pressure (BP) at rest and during CO2 breathing. Transfer function analysis was performed on resting beat-to-beat MCAv and BP to determine CA, from which phase, gain, and coherence of the BP-MCAv data were derived. Dietary nitrate elevated plasma nitrate concentration by ~420% (P < 0.001) and lowered gain (d = 1.2, P = 0.025) and phase of the BP-MCAv signal compared with placebo treatment (d = 0.7, P = 0.043), while coherence was unaffected (P = 0.122). Dietary nitrate increased the MCAv-CO2 slope in a sex-specific manner (interaction: P = 0.016). Dietary nitrate increased the MCAv-CO2 slope in men (d = 1.0, P = 0.014 vs. placebo), but had no effect in women (P = 0.919). Our data demonstrate that dietary nitrate greatly increased cerebrovascular CO2 reactivity in healthy individuals, while its effect on CA remains unclear. The selective increase in the MCAv-CO2 slope observed in men indicates a clear sexual dimorphic role of NO in cerebrovascular function.NEW & NOTEWORTHY We found dietary nitrate supplementation improved the brain blood vessels' response to CO2, cerebrovascular CO2 reactivity, without affecting blood pressure in a group of healthy individuals. Meanwhile, the effect of dietary nitrate on the relationship between blood pressure and brain blood flow, cerebral autoregulation, was inconclusive. The improvement in cerebrovascular CO2 reactivity was only observed in the male participants, alluding to a sex difference in the effect of dietary nitrate on brain blood flow control. Our findings indicate that dietary nitrate could be an effective strategy to enhance cerebrovascular CO2 reactivity.

Neurosteroid replacement therapy using the allopregnanolone-analogue ganaxolone following preterm birth in male guinea pigs.

BACKGROUND: Children born preterm, especially boys, are at increased risk of developing attention deficit hyperactivity disorder (ADHD) and learning difficulties. We propose that neurosteroid-replacement therapy with ganaxolone (GNX) following preterm birth may mitigate preterm-associated neurodevelopmental impairment. METHODS: Time-mated sows were delivered preterm (d62) or at term (d69). Male preterm pups were randomized to ganaxolone (Prem-GNX; 2.5 mg/kg subcutaneously twice daily until term equivalence), or preterm control (Prem-CON). Surviving male juvenile pups underwent behavioural testing at d25-corrected postnatal age (CPNA). Brain tissue was collected at CPNA28 and mature myelinating oligodendrocytes of the hippocampus and subcortical white matter were quantified by immunostaining of myelin basic protein (MBP). RESULTS: Ganaxolone treatment returned the hyperactive behavioural phenotype of preterm-born juvenile males to a term-born phenotype. Deficits in MBP immunostaining of the preterm hippocampus and subcortical white matter were also ameliorated in animals receiving ganaxolone. However, during the treatment period weight gain was poor, and pups were sedated, ultimately increasing the neonatal mortality rate. CONCLUSION: Ganaxolone improved neurobehavioural outcomes in males suggesting that neonatal treatment may be an option for reducing preterm-associated neurodevelopmental impairment. However, dosing studies are required to reduce the burden of unwanted side effects.

Improving pregnancy outcomes in humans through studies in sheep.

Experimental studies that are relevant to human pregnancy rely on the selection of appropriate animal models as an important element in experimental design. Consideration of the strengths and weaknesses of any animal model of human disease is fundamental to effective and meaningful translation of preclinical research. Studies in sheep have made significant contributions to our understanding of the normal and abnormal development of the fetus. As a model of human pregnancy, studies in sheep have enabled scientists and clinicians to answer questions about the etiology and treatment of poor maternal, placental, and fetal health and to provide an evidence base for translation of interventions to the clinic. The aim of this review is to highlight the advances in perinatal human medicine that have been achieved following translation of research using the pregnant sheep and fetus.

Guinea pig models for translation of the developmental origins of health and disease hypothesis into the clinic.

Over 30 years ago Professor David Barker first proposed the theory that events in early life could explain an individual's risk of non-communicable disease in later life: the developmental origins of health and disease (DOHaD) hypothesis. During the 1990s the validity of the DOHaD hypothesis was extensively tested in a number of human populations and the mechanisms underpinning it characterised in a range of experimental animal models. Over the past decade, researchers have sought to use this mechanistic understanding of DOHaD to develop therapeutic interventions during pregnancy and early life to improve adult health. A variety of animal models have been used to develop and evaluate interventions, each with strengths and limitations. It is becoming apparent that effective translational research requires that the animal paradigm selected mirrors the tempo of human fetal growth and development as closely as possible so that the effect of a perinatal insult and/or therapeutic intervention can be fully assessed. The guinea pig is one such animal model that over the past two decades has demonstrated itself to be a very useful platform for these important reproductive studies. This review highlights similarities in the in utero development between humans and guinea pigs, the strengths and limitations of the guinea pig as an experimental model of DOHaD and the guinea pig's potential to enhance clinical therapeutic innovation to improve human health.

Maternal High-Fat and High-Salt Diets Have Differential Programming Effects on Metabolism in Adult Male Rat Offspring.

Maternal high-fat or high-salt diets can independently program adverse cardiometabolic outcomes in offspring. However, there is a paucity of evidence examining their effects in combination on metabolic function in adult offspring. Female Sprague Dawley rats were randomly assigned to either: control (CD; 10% kcal from fat, 1% NaCl), high-salt (SD; 10% kcal from fat, 4% NaCl), high-fat (HF; 45% kcal from fat, 1% NaCl) or high-fat and salt (HFSD; 45% kcal from fat, 4% NaCl) diets 21 days prior to mating and throughout pregnancy and lactation. Male offspring were weaned onto a standard chow diet and were culled on postnatal day 130 for plasma and tissue collection. Adipocyte histology and adipose tissue, liver, and gut gene expression were examined in adult male offspring. HF offspring had significantly greater body weight, impaired insulin sensitivity and hyperleptinemia compared to CD offspring, but these increases were blunted in HFSD offspring. HF offspring had moderate adipocyte hypertrophy and increased expression of the pre-adipocyte marker Dlk1. There was a significant effect of maternal salt with increased hepatic expression of Dgat1 and Igfb2. Gut expression of inflammatory (Il1r1, Tnfα, Il6, and Il6r) and renin-angiotensin system (Agtr1a, Agtr1b) markers was significantly reduced in HFSD offspring compared to HF offspring. Therefore, salt mitigates some adverse offspring outcomes associated with a maternal HF diet, which may be mediated by altered adipose tissue morphology and gut inflammatory and renin-angiotensin regulation.