Oligosaccharides ameliorate insulin resistance and hepatic metabolism by promoting the leptin/POMC axis to accelerate short stature growth and development.

Bifidobacterium supplementation ameliorates LPS-induced immune stress and intestinal barrier dysfunction in goslings.

Concerns about the unintended consequences of using pesticides in agricultural settings have led to a shift in practise towards more environmentally friendly methods such as composting, manuring and using plant growth-promoting bacteria. While compost is known for its ability to promote plant growth and serve as a soil amendment, little is known about the various types of bacteria that can be found in it and how effective they are in sustainable agriculture. This study was designed to assess the potency of a few common isolates from local compost by quantifying their capacity to fix nutrients, produce growth hormone, mitigate abiotic stress, produce lignocellulose-degrading enzyme and produce soil-amending enzyme, all while scaling them using an objective in silico method. In addition, the isolates were tested in the field against test crops selected from the monocot and dicot families, namely maize (Zea mays) and okra (Abelmoschus esculentus). When comparing the treated settings to the untreated control setups, an increase was seen in the quantity of fruits (okra) and percentage of grain filling (maize). By creating a score system, an attempt was made to compare the efficiency of five strains based on the invitro and invivo experiments.

Parental benzo[a]pyrene exposure and timing of reproduction determine the magnitude and persistence of transgenerational toxicity in marine medaka (Oryzias melastigma).

Perinatal failure in the growth hormone (GH)-insulin-like growth factor-1 (IGF-1) axis causes impaired body growth and central and autonomous neurodevelopmental disorders. However, whether a primary neurodevelopmental disorder causes organ misinnervation as a contributing factor in growth retardation is elusive. To interrogate this, here we generated a late embryonic neural-specific cdc20 homolog 1 (Cdh1) knockout mouse model, which exhibited a primary delay in early postnatal brain development. These mice displayed an intact GH-releasing hormone (GHRH)-GH-hepatic GH receptor (GHR) pathway despite a body growth retardation that could be reversed by IGF-1 administration in the early postnatal life. Mechanistically, liver sympathetic misinnervation impaired signal transducers and activators of transcription 5 (STAT5) phosphorylation, required for liver IGF-1 biosynthesis and release. We also report decreased blood levels of IGF-1 in a patient harboring a pathogenic mutation in Cdh1 that causes neurodevelopmental and growth delay. Taken together, these findings demonstrate that a primary neurodevelopmental defect disrupts sympathetic hepatic innervation, leading to a GH-independent growth retardation, thus establishing a positive feedback loop that propagates the disease presentation.

Excess growth hormone (GH) production leading to acromegaly most commonly emanates from an adenomatous pituitary somatotroph. Understanding the pathogenesis of these adenomas will elucidate how biologic behavior affects acromegaly treatment outcomes. We searched PubMed for relevant English-language original research and review articles on signaling pathways and molecular drivers implicated in the pathogenesis of non-familial somatotroph adenomas in patients with acromegaly. Somatotroph cells express cognate G-protein coupled receptors for both hypothalamic stimulatory GH-releasing hormone (GHRH) and inhibitory somatostatin. Somatotroph GH transcription and secretion, as well as somatotroph cell lineage development, proliferation, and differentiation, are mediated by GHRH signaling through its cognate receptor (GHRHR), driving increased intracellular cyclic adenosine monophosphate (cAMP) levels. Point mutations in GNAS and other genomic and non-genomic aberrations in the tightly regulated GHRH-GHRHR signaling pathway result in persistent cAMP signaling, inducing GH production and somatotroph proliferation, and potentially favoring the development of sporadic somatotroph adenomas. Enhanced cAMP signaling also increases DNA damage markers and activates DNA damage response pathways, leading to a senescent adenomatous phenotype tightly linked to GH overproduction. The cAMP pathway appears to be a dominant molecular driver of somatotroph adenoma pathogenesis. Elevated cAMP drives GH hypersecretion and somatotroph proliferation and also induces DNA damage, as evidenced by increased genomic instability and a senescent signature. Collectively, these findings elucidate a molecular framework for the biological behavior of these adenomas and their responsiveness to therapies targeting cAMP-dependent pathways, including somatostatin receptor ligands.

ABSTRACT Importance Recombinant human growth hormone (rhGH) improves height in children with growth hormone deficiency (GHD). However, its metabolic effects remain unclear. Objective To synthesize evidence regarding the metabolic effects of rhGH or growth hormone (GH) derivatives in GHD, identify knowledge gaps, and highlight future research priorities. Methods PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure, China Biology Medicine disc, and Wanfang databases were searched in July 2023 to identify studies on metabolic effects of GH treatment. Bubble plots were used to visualize GH treatment effects on metabolic parameters according to treatment duration by comparison with baselines, nonpharmacological interventions, and healthy controls. Random‐effects meta‐analyses were conducted for outcomes with inconsistent findings across original studies when randomized controlled trial data were sufficient. The study was registered with INPLASY (INPLASY202450064). Results Sixty‐three studies (6158 participants) analyzed the effects of GH treatment on metabolic outcomes in children with GHD. Overall, GH treatment slightly affected glucose levels; lipid effects were inconsistent. GH treatment did not influence bone mineral density, bone mineral content, or parathyroid hormone levels. Most studies showed no significant effects on thyroid hormone levels, body composition, or body mass index (BMI). GH treatment may increase serum asymmetric dimethylarginine and gastrin levels while reducing tumor necrosis factor and serum urea levels. Interpretation Glucose and thyroid outcomes are consistent with clinical observations; effects on lipids, calcium, phosphorus, body composition, BMI, and waist‐to‐hip ratio require further validation owing to data inconsistency. New biomarkers are warranted. Further clinical studies are needed in children across age groups, GHD severities, and nutritional statuses.

Lipid nanoparticles (LNPs) play a critical role in the delivery of therapeutic messenger RNA (mRNA). Despite extensive efforts to optimize lipid formulations for in vivo delivery, efficacy of mRNA by LNPs remains suboptimal in many organs. Here, we demonstrate that LNP delivery efficacy is influenced by cellular metabolism, with the physiologic metabolome imposing constraints on mRNA expression from LNPs. Using an in vitro system, we found that simulated physiologic metabolic conditions led to the down-regulation of certain amino acid metabolic programs. Supplementation with an optimized formulation of methionine, arginine, and serine as an amino acid supplement (AAS) enhanced the uptake of LNPs and the expression of delivered mRNA cargo in epithelial cells in vitro. Coadministration of AAS with LNPs led to a 5- to 20-fold improvement in mRNA expression across various cell types and lipid formulations in vitro by promoting clathrin-independent carrier-mediated endocytosis. Delivery of mRNA by LNPs coadministered with AAS by multiple routes enhanced in vivo mRNA expression in preclinical models. Delivery of mRNA encoding growth hormone by LNPs with coadministration of AAS improved the liver growth hormone expression and the therapeutic outcomes in a model of inflammatory liver damage. Delivery of gene editing materials by LNP and AAS through an intratracheal route increased lung-targeted in vivo gene editing efficiency compared with LNP alone. The addition of an optimized AAS as a codelivered agent with LNPs may provide a simple strategy to broadly improve the efficacy of mRNA-based cell and gene therapies.

Objectives Growth hormone deficiency (GHD) in children is a significant medical condition that impairs growth and development, necessitating early intervention to mitigate potential long-term health consequences. This study aimed to assess aspects of the treatment experience, primarily focusing on adherence and patient satisfaction, as well as health-related quality of life in pediatric patients receiving long-acting growth hormone (LAGH) versus daily growth hormone (dGH) therapy. It highlights Somapacitan’s potential to revolutionize treatment adherence in affected children, offering a promising future for pediatric endocrinology. Methods: The study was conducted over 24 months at the Pediatric Endocrinology Outpatient Clinic in collaboration with King Abdulaziz University Hospital in Jeddah, Saudi Arabia. Study design: A retrospective cohort study included 494 pediatric patients diagnosed with GHD who received LAGH versus dGH. Key outcomes included increased levels of adherence and patient satisfaction with LAGH, with a statistically significant difference at P < 0.05. Results: The patients had a mean age of 11.29 years, with a predominantly male population (64.6%). A large proportion of patients, 46.6%, received LAGH, and 60.5% had been receiving growth hormone therapy for more than 12 months. Early observations following LAGH reveal a substantial and statistically significant increase in adherence (99.56%) and patient satisfaction with the frequency of injection ( P = 0.000). Additionally, improvement was noticed in health-related quality of life, self-esteem, and socialization, favoring LAGH. Conclusion: A weekly dosing regimen reduced the burden of daily injections, leading to higher adherence rates and patient satisfaction, thus improving patients’ health-related quality of life.

Although early diagnosis is underutilized in many care settings, children with growth hormone (GH) disorders have developmental delays, obesity, and high costs that are rising globally. This study examines the costs and outcomes of the innovative approaches such as the GH/BMI Screening Interventions on the health and social development of children In LMICs. In the cross-sectional study which was conducted in a multi-center setting, a sample of 1000 children aged between 1 and 10 from multiple countries were enrolled. The collection of the sample, preprocessing, designing of the experiment, and all the statical analyses were done in a systematic manner. The Pre-Development Screening Questionnaire (KPSP) was administered at the beginning of the intervention and periodical intervals and intervals of 3 months to measure mass index, plasma development hormone, and plasma thyroid-stimulating hormone (TSH) levels and developmental milestones attained, in the framework of the 1-year period on the environmental change, muscle activity via exercises, and the guidelines on food to be consumed. The preprocessing of the data included quality control, normalization, and imputation of missing data. Statistical analyses were performed using SPSS v26 and included descriptive statistics, paired t-test, ANOVA, multiple linear regression, and Pearson correlation. The results revealed that there were statistically significant modulations in each of the measured parameters with GH level increased 311% (i.e., from 1.59 ± 0.83 to 6.54 ± 0.87 ng/mL), TSH to be raised up to 5.04 ± 0.32 μIU/ml which could represent higher thyroid function activities, and BMI decreased by about twenty percent (from23.94±0.56to19.23±0.43 kg/m²;all p<:0001). The developmental score improved significantly (R² = 0.65), with BMI decrease and GH increase representing the major most powerful predicting factors at outcome. The cost-benefit analysis modelled significant reductions in health care costs with application to other pediatric populations. Early GH and BMI screening, and application of non-pharmacological measures have strong potential to improve health and save healthcare costs as well as promote social development confirming on separately international pediatric healthcare systems.

Administering Bacilli clausii as probiotics during the maternal period may enhance microbial balance and positively impact offspring growth and immune health. This study evaluated the influence of Bacillus given to pregnant mice on the growth and immune development of their male albino offspring at 28days old. Twenty-four Swiss albino mice (16 females and 8 males) were mated and assigned to four groups. Sixteen pregnant mice were divided into four groups (n = 4/group). The control group received a standard diet with distilled water, while the other three groups received daily doses of Bacilli (1.25mL at 1 × 10^9CFU) at different pregnancy stages: the second group on gestational day (GD) 0, the third on GD 8, and the fourth on GD 16. At 28days after birth, male offspring were weighed, and blood samples were collected. The EDTA samples were used for hematological profiles, while serum samples were analyzed for growth hormone (GH), insulin-like growth factor-1 (IGF-1), tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), interleukin-10 (IL-10), and immunoglobulins (IgA and IgG). Spleens were weighed and analyzed for mTOR using qPCR, ELISA, and histological analysis and immunohistochemical staining for IGF-1 and FOXO1 markers. The GD0 group showed significant increases in body weight, spleen weight, spleen somatic index (SSI), GH, IGF-1, IL-10, IgA, and IgG levels, as well as mTOR protein and transcript levels, while TNF-α and IFN-γ levels decreased. Macroscopic analysis revealed a well-structured white pulp containing aggregated lymphocytes. Elevated levels of IGF-1 expression were observed, while FOXO1 expression was decreased. These findings indicate that early maternal probiotic supplementation improves lymphocyte activity and facilitates the remodeling of the splenic immune system in offspring and thus represents an innovative approach to immune programming during early life.

ABSTRACT Early-life stressors may increase susceptibility to adverse environments in adulthood. The aim of this study was to assess homeostatic responses to a physical stressor, heat, in offspring perinatally exposed to environmental and/or dietary stressors. Female CD-1-mice were exposed to 0 ppm cadmium (Cd) with control diet, Cd (0.5 ppm in drinking water with control diet), or 0 ppm Cd with 59% high-fructose (HFr) diet three-weeks pre-mating through postnatal day 16. Offspring (17–21-week-old) were exposed 3 hr to either room-temperature, RT, 21°C; mid-temperature, MT, 30°C; or high-temperature, HT, 37°C (n = 12/sex/group). Maternal HFr reduced postnatal bodyweight in both sexes. Cadmium-exposed males exhibited lower HDL and cholesterol levels, whereas females displayed increased adrenocorticotrophic hormone (ACTH) and leptin levels. HT elevated serum triglycerides concentrations, reduced lymphocyte number, and increased neutrophils regardless of developmental exposure in both sexes. HT elevated serum free fatty acids levels in offspring with exacerbation in Cd and HFr females. HT reduced levels of ACTH and glucose and increased growth hormone in HFr males but decreased glucose in Cd-exposed females. HT-induced immune cell changes were attenuated in HFr males. In females, leptin levels were elevated in HT controls and lowered in HT+HFr with decreased glucose observed in HT+Cd. HT diminished prolactin concentrations in controls and HT+HFr but not Cd-exposed females. HT induced an acute neuroendocrine stress response and associated metabolic/immune changes which were selectively modified by sex and developmental exposure to Cd or HFr diet.

SUMMARY For the past thirty years, the daily recombinant human growth hormone (rhGH) therapy such as Somatropin has been demonstrated to be safe and effective and has been widely used for pediatric growth hormone deficiency (pGHD) and other growth failure conditions in children. More recently, several long-acting recombinant human growth hormone (LAGH) have also been developed or are close to regulatory approval to decrease the inconvenience of daily injections and increase treatment adherence through once weekly administration (Grillo et al., 2023). Somatrogon is an example of one such LAGH which was approved by FDA for pGHD indication in June 2023. A randomized Phase 3 study was conducted and demonstrated non-inferiority (NI) of Somatrogon compared to daily Somatropin for pGHD patients. It is of interest to study Somatrogon in other conditions involving growth failure in children. These include Small for Gestational Age (SGA), Idiopathic Short Stature (ISS) and Turner Syndrome (TS). All these conditions result in growth failure, albeit because of different etiologies. We propose a single study which utilizes a master protocol design that promotes efficiencies for the Sponsor, investigators, study participants, and regulatory agencies and a novel application of the meta-analysis across the multiple indications. This single master protocol approach provides the framework by which we are able to evaluate a common intervention across multiple indications in parallel, which is an innovative and efficient alternative to the standard series of clinical trials that typically investigate one intervention in a disease in a single study. The study design and statistical methodologies are described. Simulations are also presented to compare study power under different scenarios.

Traumatic brain injury (TBI), a growing public health concern worldwide, has recently been recognized as one of the most common etiologies of hypopituitarism. Leading causes of TBI-induced pituitary dysfunction include road traffic accidents, falls, domestic violence, sport-related injuries and war injuries. The prevalence of hypopituitarism after TBI is about 15% and growth hormone is the most common pituitary hormone deficiency after TBI. Because the clinical spectrum of TBI-induced pituitary dysfunction is broad and most of the manifestations are nonspecific, the diagnosis is often delayed and many patients remain undiagnosed and untreated. Current evidence show that pituitary hormone deficiencies seen in patients with mild and moderate TBI may improve over time in a considerable number of patients, but some may also worsen over time. Since not all TBI patients develop pituitary dysfunction, testing all patients with a history of TBI is not realistic and cost-effective. Predictive factors of post-TBI hypopituitarism including number of hormone deficiencies during acute phase, radiological abnormalities, genetic polymorphism, older age, female gender should be taken into account for development of screening strategies. Prospective screening of pituitary functions is required in complicated mild TBI (defined as clinically mild by all severity measures but considered complicated due to a traumatic intracranial abnormality visible on neuroimaging), moderate and severe TBI patients. Increased awareness of TBI-induced hypopituitarism in the medical community may lead to earlier diagnosis and prompt treatment of hypopituitarism with appropriate replacement of deficient hormones.

Dento-maxillofacial abnormalities are highly prevalent and arise as a result of a variety of etiological factors, presenting substantial challenges to treatment. The JAK-STAT signaling plays a pivotal role in dentofacial development, regulating endochondral ossification, intramembranous ossification, dental follicle formation, and enamel development. Mutations in the JAK-STAT signaling lead to syndromes associated with severe dento-maxillofacial abnormalities, including Growth Hormone Insensitivity Syndrome and Autosomal Dominant Hyper-IgE Syndrome. Corresponding mouse disease models have been developed to simulate the phenotypes observed in clinical patients and investigate their underlying mechanism. Meanwhile, several medications targeting JAK-STAT signaling, including baricitinib and imatinib, have been developed for clinical application, demonstrating significant effects in skeletal disorders such as osteoporosis and osteoarthritis, indicating promising effects in development and abnormalities of dento-maxillofacial. In this review, we aim to summarize the role of JAK-STAT signaling in the development and abnormalities of dento-maxillofacial bone, and the relevant molecules that may be utilized for clinical treatment, to shed new light on the precise treatment of dento-maxillofacial abnormalities.

Short stature in children born small for gestational age (SGA) is treated with daily injections of recombinant growth hormone (GH), a significant treatment burden. The objective of this study is to demonstrate the efficacy and safety of once-weekly somapacitan, a long-acting GH, in short children born SGA. REAL8 (NCT05330325) is a multinational, multicenter, randomized, open-labeled, active comparator, phase 3 basket study including four non-GH deficiency indications comprising a 52-week main phase and 104-week extension. Here, we present 52-week results from the SGA sub-study. 142 prepubertal, treatment-naïve children born SGA in 78 sites across 26 countries were randomized 2:1:1 to somapacitan .24 mg/kg/week or daily GH 0.035 or 0.067 mg/kg/day, all administered subcutaneously. 140 completed the main 52-week treatment period. The primary endpoint, estimated mean height velocity at week 52, was 11.0 cm/year for somapacitan vs. 9.4 cm/year [ETD = 1.6(0.91, 2.23)95%CI] and 11.1 cm/year [ETD = -0.1(-0.75, 0.60)95%CI] for daily GH 0.035 and 0.067 mg/kg/day, respectively. Noninferiority was confirmed for somapacitan compared to both daily GH groups. Superiority was demonstrated for somapacitan versus daily GH 0.035 mg/kg/day. Safety profiles were similar between treatment groups. As expected, somapacitan reduced disease burden at week 52, as for daily GH 0.067 mg/kg/day, while somapacitan was associated with reduced treatment burden. Somapacitan provides similar efficacy, safety, and tolerability as daily GH in short children born SGA after 52 weeks of treatment. Somapacitan may be an attractive alternative to daily GH in this population, reducing treatment burden to improve adherence and treatment outcomes.

N/A

Introduction and aim: Acromegaly is a chronic endocrine disorder caused by sustained excess secretion of growth hormone and insulin-like growth factor I, leading to significant morbidity and increased mortality if inadequately treated. Transsphenoidal surgery remains the primary therapeutic approach; however, a substantial proportion of patients fail to achieve durable biochemical remission and require long-term medical therapy. Injectable somatostatin receptor ligands are effective but are associated with treatment burden, variable biochemical responses, and impaired quality of life. The aim of this review was to summarize current management strategies for acromegaly and to evaluate the emerging role of paltusotine, a novel orally administered somatostatin receptor agonist. Materials and Methods: This narrative review was based on a structured analysis of published clinical trials, extension studies, and review articles evaluating the pharmacological properties, clinical efficacy, and safety of paltusotine in patients with acromegaly. Results: Available evidence indicates that paltusotine provides effective suppression of growth hormone secretion and reduction of insulin-like growth factor I levels with once-daily oral administration. Clinical studies demonstrate maintenance of biochemical control in patients previously treated with injectable therapies, as well as efficacy in selected untreated individuals. Paltusotine was generally well tolerated, with predominantly mild gastrointestinal adverse events and elimination of injection-related complications. Conclusions: Paltusotine represents a promising oral alternative to injectable somatostatin receptor ligands, with the potential to reduce treatment burden, improve adherence, and maintain biochemical control. Further long-term and real-world studies are needed to fully define its role in routine clinical practice.

Central hypothyroidism, a hypothyroid state resulting from insufficient stimulation by thyrotropin (TSH) of an otherwise normal thyroid gland, is a rare under-recognized side effect of oxcarbazepine. We describe four young patients diagnosed with central hypothyroidism likely due to oxcarbazepine and conducted a literature review for previously published cases. Four patients ranging in age from 11-20 years were treated with oxcarbazepine and were subsequently found to have low free thyroxine (FT4) levels and inappropriately normal thyroid stimulating hormone (TSH) concentrations. All had normal thyroid examinations and normal morning cortisol. The two patients who were still growing had normal growth hormone markers. Magnetic resonance imaging (MRI) of the brain was normal in all. Three of the patients experienced symptoms consistent with hypothyroidism; treatment with levothyroxine led to resolution of symptoms. Three of the patients discontinued oxcarbazepine; subsequently all had normalization of thyroid function. Oxcarbazepine can lead to low FT4 concentrations with normal TSH values. Assessment of TSH and FT4 could be included in the periodic screening of patients taking oxcarbazepine. A limited number of reported cases have suggested that monitoring of thyroid function studies may be indicated in patients taking oxcarbazepine, to monitor for development of CH.

Background/Objectives: The potential of outdoor physical activity as an intervention strategy to promote height growth velocity via stimulating growth hormone secretion and vitamin D synthesis has been scarcely investigated. The present study aimed to investigate the associations between outdoor physical activity duration and height growth velocity, and differences in gender, age, exposure time period (daily, school days vs. weekends), and body mass index (BMI) category. Methods: We performed a secondary analysis of longitudinal data from the 2019-2020 Chinese National Survey on Students' Constitution and Health. The analytic sample included 5029 adolescents aged 9-18 years. High or low height growth velocity was defined as sex- and age-specific percentiles. Associations of high height growth velocity with outdoor activity duration (≥1 h, ≥2 h) on school days and weekends were investigated using multivariable logistic regression models. Analyses were stratified by sex, age group (9-12, 13-15, 16-18 years), and BMI category (normal weight, overweight, and obese). Results: Results from this cross-sectional analysis indicate that ≥1 h of daily outdoor physical activity is significantly associated with higher height growth velocity among normal-weight boys aged 9-15 years (OR range: 1.71-2.01) and girls aged 9-12 years (OR = 1.68). The positive association increased with ≥2 h (ORs up to 7.96). Consistently positive associations were found for activity during the school day compared to weekends. No significant associations were found in overweight and obese children. Conclusions: Ensuring adequate daily outdoor physical activity-especially on weekends-for at least two hours may be an important potential strategy to promote height growth in normal-weight children and adolescents. Interventions should consider differences in weight status and timing of activity.