Cyclic Glycine-proline Research Articles

Enhancement of memory and reduction of amyloid plaques in alzheimer\'s disease mouse model using cyclic glycine-proline

Amyloid plaques and neurofibrillary tangles are two of the most important signs that can be used to diagnose Alzheimer's disease (AD), which is a neurodegenerative condition. Animal models, such as APP/PS1 mice, are extremely important for advancing our understanding of the factors that contribute to Alzheimer's disease and evaluating potential treatments. The purpose of this study is to investigate the effects of cyclic glycine-proline (cGP), a stable cyclic dipeptide that originates from glutamate, on spatial memory and the accumulation of amyloid plaque in mice with Alzheimer's disease and Parkinson's disease type 1.In order to evaluate the spatial memory of APP/PS1 mice, the Morris Water Maze was utilised after the mice had been administered cGP. To determine the amount of amyloid plaque in the brain, first the staining was done using thioflavin-S, then imaging was performed, and last the results were quantified. Treatment with cGP resulted in a considerable reduction in the quantity of amyloid plaque and an improvement in spatial memory in mice with APP/PS1 mutations. There was a decline in escape latency times, amyloid plaque numbers, and plaque covering percentages in the cortex and hippocampus.There is evidence to suggest that cGP may have therapeutic potential; in a rat model of Alzheimer's disease, it was found to improve cognitive performance and reduce amyloid pathology. The therapeutic potential of cGP in reducing AD pathology and cognitive impairment is demonstrated by these results.

Quantitative Monitoring of Cyclic Glycine-Proline in Marine Mangrove-Derived Fungal Metabolites.

This study developed and validated a robust UPLC-MS/MS method for quantifying cyclic glycine-proline (cGP) in mangrove-derived Penicillium and Aspergillus strains. The method demonstrated excellent linearity, precision, and recovery, with detection limits as low as 4.8 ng/mL. Penicillium pedernalense extract achieved a cGP content of 67.45 ± 1.11 ng/mL, with a corresponding fermentation yield of 29.31 ± 0.61 mg/L. This surpassed Penicillium steckii, which reached a content of 31.71 ± 0.31 ng/mL, with a yield of 8.51 ± 0.15 mg/L. This quantitative approach for metabolite analysis provides a viable method for screening these fungal strains, highlighting their potential for sustainable production of cyclic glycine-proline (cGP).

Exploring Sources, Biological Functions, and Potential Applications of the Ubiquitous Marine Cyclic Dipeptide: A Concise Review of Cyclic Glycine-Proline.

Cyclic glycine-proline (cGP), a prevalent marine cyclic dipeptide, possesses a distinct pyrrolidine-2,5-dione scaffold, which contributes to the chemical diversity and broad bioactivities of cGP. The diverse sources from marine-related, endogenous biological, and synthetic pathways and the in vitro and in vivo activities of cGP are reviewed. The potential applications for cGP are also explored. In particular, the pivotal roles of cGP in regulating insulin-like growth factor-1 homeostasis, enhancing neuroprotective effects, and improving neurotrophic function in central nervous system diseases are described. The potential roles of this endogenous cyclic peptide in drug development and healthcare initiatives are also highlighted. This review underscores the significance of cGP as a fundamental building block in drug discovery with exceptional drug-like properties and safety. By elucidating the considerable value of cGP, this review aims to reignite interest in cGP-related research within marine medicinal chemistry and synthetic biology.

Cyclic Glycine-Proline Improves Memory and Reduces Amyloid Plaque Load in APP/PS1 Transgenic Mouse Model of Alzheimer's Disease.

Alzheimer's disease (AD) is a neurodegenerative condition that is pathologically characterized by the presence of amyloid plaques and neurofibrillary tangles. Animal models of AD have been useful in understanding the disease process and in investigating the effects of compounds on pathology and behavior. APP/PS1 mice develop amyloid plaques and show memory impairment. Cyclic glycine-proline (cGP) is a cyclic dipeptide that is likely produced from a tripeptide, glycine-proline-glutamate, which itself is generated after proteolytic cleavage of insulin-like growth factor-1. Here, we show that cGP improves spatial memory and reduces amyloid plaque burden in APP/PS1 mice. The results thus suggest that cGP could potentially provide beneficial effects in AD.

Cyclic Glycine-Proline (cGP) Normalises Insulin-Like Growth Factor-1 (IGF-1) Function: Clinical Significance in the Ageing Brain and in Age-Related Neurological Conditions.

Insulin-like growth factor-1 (IGF-1) function declines with age and is associated with brain ageing and the progression of age-related neurological conditions. The reversible binding of IGF-1 to IGF binding protein (IGFBP)-3 regulates the amount of bioavailable, functional IGF-1 in circulation. Cyclic glycine-proline (cGP), a metabolite from the binding site of IGF-1, retains its affinity for IGFBP-3 and competes against IGF-1 for IGFBP-3 binding. Thus, cGP and IGFBP-3 collectively regulate the bioavailability of IGF-1. The molar ratio of cGP/IGF-1 represents the amount of bioavailable and functional IGF-1 in circulation. The cGP/IGF-1 molar ratio is low in patients with age-related conditions, including hypertension, stroke, and neurological disorders with cognitive impairment. Stroke patients with a higher cGP/IGF-1 molar ratio have more favourable clinical outcomes. The elderly with more cGP have better memory retention. An increase in the cGP/IGF-1 molar ratio with age is associated with normal cognition, whereas a decrease in this ratio with age is associated with dementia in Parkinson disease. In addition, cGP administration reduces systolic blood pressure, improves memory, and aids in stroke recovery. These clinical and experimental observations demonstrate the role of cGP in regulating IGF-1 function and its potential clinical applications in age-related brain diseases as a plasma biomarker for-and an intervention to improve-IGF-1 function.

Administration of cyclic glycine-proline during infancy improves adult spatial memory, astrocyte plasticity, vascularization and GluR-1 expression in rats

ABSTRACT Cyclic glycine-proline (cGP) is a natural nutrient of breast milk and plays a role in regulating the function of insulin-like growth factor-1 (IGF-1). IGF-1 function is essential for post-natal brain development and adult cognitive function. We evaluated the effects of cGP on spatial memory and histological changes in the hippocampus of the adult rats following infancy administration. Infant rats were treated with either cGP or saline between post-natal days 8 and 22 via oral administration to lactating dams. The spatial memory was evaluated between post-natal days 70 and 75 using Morris water maze tests. The changes of capillaries, astrocytes, synaptophysin and glutamate receptor-1 were examined in the CA1 stratum radiatum of the hippocampus. Compared to saline-treated group, cGP-treated group showed higher path efficiency of entry and lower average heading errors to the platform zone. cGP-treated group also showed longer, larger and more astrocytic processes, more capillaries and higher glutamate receptor-1 expression. The rats made less average heading error to the platform zone have more capillaries, larger and longer astrocytic branches. Thus cGP treatment/supplementation during infancy moderately improved adulthood spatial memory. This long-lasting effect of cGP on memory could be mediated via promoting astrocytic plasticity, vascularization and glutamate trafficking. Therefore, cGP may have a role in regulating IGF-1 function during brain development.

The autocrine regulation of insulin-like growth factor-1 in human brain of Alzheimer’s disease

BackgroundInsulin-like growth factor (IGF) binding protein (IGFBP)−3 and cyclic Glycine-Proline (cGP) regulate circulating IGF-1 function that is associated with cognition. The association between IGF-1 function and Alzheimer’s disease (AD) remains inconclusive. This study evaluated the changes of IGFBPs and cGP, and their effects on the bioavailability and function of IGF-1 in human brain of AD cases. MethodsUsing biological and mathematic analysis we measured the concentrations of total, bound and unbound forms of IGF-1, IGFBPs and cGP in the inferior-frontal gyrus and middle-frontal gyrus of human AD (n = 15) and control cases (n = 15). The association between the changes of total concentration of these peptides and total protein concentration in brain tissues were also analyzed. ResultsThe unbound bioavailable IGF-1 was lower whereas the bound cGP and IGFBP-3 were higher in AD than the control cases. Total protein that was lower in AD than control cases, was negatively associated with cGP concentration of control cases and with IGFBP-3 concentration of AD cases. ConclusionsThe results provide direct evidence for IGF-1 deficiency in AD brain due to lower bioavailable IGF-1. The increase of bound IGFBP-3 impaired autocrine regulation. The increase of bound cGP is an autocrine response to improve the bioavailability and function of IGF-1 in AD brain. Availability of data and materialAll data generated or analysed during this study are included in this published article. Additional datasets analysed during the current study available from the corresponding author on reasonable request.

Growth Factor Concentrations in Human Milk Are Associated With Infant Weight and BMI From Birth to 5 Years.

Background: Human milk bioactives may play a role in infant health and development. Although the variability in their concentrations in milk is well-established, the impact of differential milk profiles on infant growth outcomes remains unclear. Thus, the aim of the present study was to investigate whether different concentrations of metabolic hormones are associated with different weight and BMI in infants beyond the first year of life.Methods: Milk samples at 2.6 (±0.4) months after birth and anthropometric measures at 13 months, 2, 3, and 5 years were collected as part of the Finnish STEPS cohort study from 501 mothers and the respective 507 infants. Leptin, adiponectin, insulin-like growth factor (IGF)-1 and cyclic glycine-proline (cGP) in milk were analyzed. Multiple regression models and a repeated measures mixed model were used to examine associations between milk hormone concentrations and weight and BMI z-scores across time, at each time-point, and weight gain from birth to each follow-up visit. All models were corrected for birth weight, infant sex, duration of exclusive and total breastfeeding, time of introduction of solid foods and maternal pre-pregnancy BMI.Results: Higher milk IGF-1 was associated with higher weight at 13 months (p = 0.004) but lower weight at 3 (p = 0.011) and 5 years of age (p = 0.049). Higher cGP was associated with lower weight across the 5 years (p = 0.019) but with higher BMI at 5 years (p = 0.021). Leptin and adiponectin did not display associations with infant growth at this time. Sex interactions were also absent.Conclusions: Our results suggest that the interplay between human milk-borne IGF-1 and cGP is similar to that reported in other mammals and may have an important role in defining infant growth trajectories beyond the first year of life. Further research should explore the determinants and origins of these milk-borne compounds and evaluate their effect on infant growth and metabolism.

Sexually Dimorphic Associations between Maternal Factors and Human Milk Hormonal Concentrations

While human milk composition is characterised by marked dynamicity, we are far from having a clear picture of what factors drive this variation. Hormones in human milk are known to vary according to specific maternal phenotypes, but limited evidence shows the infant also has a role in determining milk composition. The present study aimed to investigate the interplay between maternal and infant characteristics in relation to human milk hormonal profile. In total, 501 human milk samples from mothers recruited in the Finnish STEPS cohort study (Steps to the healthy development) were analysed. Pre-pregnancy and pregnancy maternal data, socioeconomic status and infant characteristics at birth were collated. Leptin, adiponectin, insulin-like growth factor-1 and cyclic Glycine-Proline in milk were measured. Multivariate analysis of variance (MANOVA) and linear regression were utilised for statistical analysis. Sex-specific interactions with maternal factors were observed, as the infant sex mediated associations between gestational diabetes and milk adiponectin (p = 0.031), birth-mode and total protein (p = 0.003), maternal education and insulin-like growth factor-1: cyclic Glycine-Proline ratio (p = 0.035). Our results suggest that changes in human milk composition are associated with interactions between maternal and infant characteristics and pathophysiological factors. Future work should expand on these findings and further explore the link between hormonal profiles in human milk and infant outcomes.

Changes of plasma cGP/IGF-1 molar ratio with age is associated with cognitive status of Parkinson disease.

ObjectiveCognitive impairment is a common feature of Parkinson disease (PD), for which age is a major contributing factor. Insulin‐like growth factor‐1 (IGF‐1) declines with age and contributes to age‐related cognitive impairment in PD. Cyclic glycine‐proline (cGP) is a metabolite of IGF‐1 and normalizes bioavailable IGF‐1. Plasma cGP/IGF‐1 molar ratio that represents bioactive IGF‐1 in circulation, may associate with the cognitive status in PD.MethodsWe examined the association of plasma cGP/IGF‐1 molar ratio with the cognitive scores or age in PD patients with normal cognition (PD‐N, n = 74), mild cognitive impairment (PD‐MCI, n = 71), or dementia (PD‐D, n = 33), and with the cognitive scores in 23 age‐matched healthy controls. Plasma concentrations of IGF‐1, IGF binding protein‐3, and cGP were evaluated using enzyme‐linked immunosorbent assay (ELISA) and high‐performance liquid chromatography‐mass spectrometry (HPLC‐MS), respectively.ResultsThe cGP/IGF‐1 molar ratio was positively correlated with the age of PD‐N group, negatively correlated with the age of PD‐D group, and not associated with the age of PD‐MCI group. Independent of age, the cGP/IGF‐1 molar ratio was positively correlated with the cognitive scores of healthy controls, but not in PD groups.ConclusionOld healthy people with a higher cGP/IGF‐1 molar ratio showed better preserved cognition, possibly due to improved IGF‐1 function. Increased cGP/IGF‐1 molar ratio with age may contribute to cognitive retention in the PD‐N group. The absence or reversal of such association with age in the PD‐MCI and PD‐D groups may indicate the conversion of cognitive status in PD, if confirmed through longitudinal investigations within the individuals with advancing cognitive impairment.

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

Background and aimsInsulin-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. MethodsMale 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. ResultsCompared 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. ConclusionHFD-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.

Cyclic glycine-proline administration normalizes high-fat diet-induced synaptophysin expression in obese rats

Childhood metabolic disorders are associated with insulin-like growth factor (IGF)-1 deficiency, which can adversely affect brain development and function. As a neuropeptide, cyclic glycine-proline (cGP) improves IGF-1 function in brain and regulates IGF-1 bioavailability in plasma. Whether such a regulatory process mediates the neurotrophic effects of cGP remains unknown. This study examined the effects cGP treatment on synaptic expression and their association with IGF-1, IGF binding protein (IGFBP)-2 and cGP concentrations in the brain of rats with high fat diet (HFD)-induced obesity.Male rats received either a HFD or a standard chow diet (STD) from weaning and were then treated with either saline or cGP from 11 to 15 weeks of age. The concentrations of cGP, IGF-1 and IGFBP-2 were measured in the brain tissues using ELISA and HPLC-MS. The expressions of synaptic markers were evaluated in the hippocampus, hypothalamus and striatum using immunohistochemical staining.Compared to the STD group, IGF-1 and IGFBP-2, but not cGP concentrations, were lower in the HFD groups. The expression of hippocampal synaptophysin, glutamate receptor-1, GFAP and striatal tyrosine-hydroxylase were also reduced in the HFD groups. While treatment did not alter tissue IGF-1, cGP administration that increased the concentration of cGP in brain tissues, normalized the expression of synaptophysin, GFAP and tyrosine-hydroxylase, but not glutamate receptor-1. IGF-1 concentration in brain tissues correlated with the expression of all synaptic markers.HFD feeding reduced synaptic expression and tissue IGF-1 in brains which were closely associated, thus suggesting IGF-1 in the brain is largely bioavailable. Without increasing IGF-1 in the brain, administration of cGP normalized synaptic expression, possibly be mediated through increasing bioavailable IGF-1, but further studies are required to confirm this.

Rett Syndrome: Treatment with IGF-I, Melatonin, Blackcurrant Extracts, and Rehabilitation

(1) This study describes the good evolution of a 6-year-old girl genetically diagnosed (R106X) with Rett syndrome (RTT), after having been treated with IGF-I, melatonin (MT), blackcurrant extracts (BC) and rehabilitated for 6 months. (2) The patient stopped normal development in the first year of age. The patient showed short stature and weight and fulfilled the main criteria for typical RTT. Despite her young age, there was pubic hair (Tanner II), very high plasma testosterone, and low levels of plasma gonadotrophins. There were no adrenal enzymatic deficits, and abdominal ultrasound studies were normal. The treatment consisted of IGF-I (0.04 mg/kg/day, 5 days/week, subcutaneous (sc)) for 3 months and then 15 days of rest, MT (50 mg/day, orally, without interruption) and neurorehabilitation. A new blood test, after 3 months of treatment, was absolutely normal and the pubic hair disappeared (Tanner I). Then, a new treatment was started with IGF-I, MT, and BC for another 3 months. In this period, the degree of pubertal development increased to Tanner III (pubic level), without a known cause. (3) The treatment followed led to clear improvements in most of the initial abnormalities, perhaps due to the neurotrophic effect of IGF-I, the antioxidant effects of MT and BC, and the cerebral increase in the cyclic glycine-proline (cGP) achieved with administration of BC. (4) A continuous treatment with IGF-I, MT, and BC appears to be useful in RTT.

Maternally Administered Cyclic Glycine-Proline Increases Insulin-Like Growth Factor-1 Bioavailability and Novelty Recognition in Developing Offspring.

Cyclic glycine-proline (cGP), a metabolite of IGF-1, is an endogenous neuropeptide that improves memory in adult rats. The presence and concentrations of endogenous cGP, and its association with IGF-1 and IGF binding protein-3 (IGFBP-3) in rat milk and plasma, were evaluated during postnatal development. Maternal-infantile transfer of cGP during lactation and its efficacy on the memory of developing offspring were also investigated. Dams were gavaged with either cGP (3 mg/kg) or saline daily from postnatal days 8-22. Concentrations of cGP were measured in dams' milk, and concentrations of cGP, IGF-1, and IGFBP-3 were measured in the plasma of dams, pups, and young adults. The recognition memory, locomotor function, and anxiety-like behavior of offspring were evaluated using behavioral tests. Endogenous cGP was detected in rat milk, and its concentration was higher during peak lactation compared with late lactation. Comparisons within control groups showed low endogenous IGF-1 and IGFBP-3 and high endogenous cGP concentrations in the plasma of male pups. The reduced IGFBP-3 and increased cGP may be a response to increase the bioavailability of IGF-1 during infancy. Exogenous cGP showed oral bioavailability and effective maternal-infantile transfer through milk. Maternally transferred cGP also led to improved recognition memory in the developing offspring, possibly through increased IGF-1 bioavailability, with no effect on locomotor activity and anxiety-like behavior. These results show that cGP is an essential endogenous peptide during early postnatal development as it improves the bioavailability of IGF-1 during infancy. Furthermore, maternal cGP supplementation offers an effective and natural route of administration for improving memory in the developing offspring.

OR2-6: Cyclic glycine-proline is a regulator that dynamically controls IGF-1 homeostasis through altering IGF-1 binding to IGFBP3

OR2-6: Cyclic glycine-proline is a regulator that dynamically controls IGF-1 homeostasis through altering IGF-1 binding to IGFBP3

Cyclic glycine-proline regulates IGF-1 homeostasis by altering the binding of IGFBP-3 to IGF-1

The homeostasis of insulin-like growth factor-1 (IGF-1) is essential for metabolism, development and survival. Insufficient IGF-1 is associated with poor recovery from wounds whereas excessive IGF-1 contributes to growth of tumours. We have shown that cyclic glycine-proline (cGP), a metabolite of IGF-1, can normalise IGF-1 function by showing its efficacy in improving the recovery from ischemic brain injury in rats and inhibiting the growth of lymphomic tumours in mice. Further investigation in cell culture suggested that cGP promoted the activity of IGF-1 when it was insufficient, but inhibited the activity of IGF-1 when it was excessive. Mathematical modelling revealed that the efficacy of cGP was a modulated IGF-1 effect via changing the binding of IGF-1 to its binding proteins, which dynamically regulates the balance between bioavailable and non-bioavailable IGF-1. Our data reveal a novel mechanism of auto-regulation of IGF-1, which has physiological and pathophysiological consequences and potential pharmacological utility.