Growth Hormone Release Research Articles

A GHRHR founder mutation causes isolated growth hormone deficiency type IV in a consanguineous Pakistani family.

Isolated growth hormone deficiency (IGHD) is caused by a severe shortage or absence of growth hormone (GH), which results in aberrant growth and development. Patients with IGHD type IV (IGHD4) have a short stature, reduced serum GH levels, and delayed bone age. To identify the causative mutation of IGHD in a consanguineous family comprising four affected patients with IGHD4 (MIM#618157) and explore its functional impact in silico. Clinical and radiological studies were performed to determine the phenotypic spectrum and hormonal profile of the disease, while whole-exome sequencing (WES) and Sanger sequencing were performed to identify the disease-causing mutation. In-silico studies involved protein structural modeling and docking, and molecular dynamic simulation analyses using computational tools. Finally, data from the Qatar Genome Program (QGP) were screened for the presence of the founder variant in the Qatari population. All affected individuals presented with a short stature without gross skeletal anomalies and significantly reduced serum GH levels. Genetic mapping revealed a homozygous nonsense mutation [NM_000823:c.G214T:p.(Glu72*)] in the third exon of the growth-hormone-releasing hormone receptor gene GHRHR (MIM#139191) that was segregated in all patients. The substituted amber codon (UAG) seems to truncate the protein by deleting the C-terminus GPCR domain, thus markedly disturbing the GHRHR receptor and its interaction with the growth hormone-releasing hormone. These data support that a p.Glu72* founder mutation in GHRHR perturbs growth hormone signaling and causes IGHD type IV. In-silico and biochemical analyses support the pathogenic effect of this nonsense mutation, while our comprehensive phenotype and hormonal profiling has established the genotype-phenotype correlation. Based on the current study, early detection of GHRHR may help in better therapeutic intervention.

Online large volume sample staking preconcentration and separation of enantiomeric GHRH analogs by capillary electrophoresis.

A capillary electrophoresis method is proposed to analyze the four most well-known growth hormone-releasing hormone (GHRH) analogs that are misused by athletes. Dimethyl-β-cyclodextrin used as a chiral selector allowed, for the first time, the separation of those basic peptide analogs, including enantiopeptides (sermorelin and CJC-1293) that differ by the chirality of only one amino acid. To increase the method sensitivity, electrokinetic preconcentration methods have been investigated. The large volume sample stacking with polarity switching (PS-LVSS) method with an injected sample volume corresponding to 80% of the capillary one was found superior to the sweeping in terms of signal enhancement factor (SEF). Acid and organic solvent addition to the sample (0.1mM phosphoric acid with 30% methanol) led to a twofold signal improvement, when compared to water as a matrix. We increased capillary dimensions to provide a signal enhancement through the injection of a larger sample volume. Finally, using a combination of the optimized PS-LVSS preconcentration with the chiral capillary zone electrophoresis (CZE), the GHRH analogs were separated and limits of detection between 75 and 200ng/mL were reached. This method was successfully applied to urine after a desalting step. An optimized C18 SPE was used for that purpose in order to provide low sample conductivity (<130µS/cm) and preserve the efficiency of LVSS preconcentration. SEF of 640 was obtained with desalted urine spiked with sermorelin by comparison to the CZE (without preconcentration) method.

Оцінка ризику розвитку соматотропної недостатності залежно від розподілу частот алелей і генотипів поліморфного локусу rs1544410 BsmI гена рецептора вітаміну D

Growth hormone deficiency (GHD) is a disease caused by a significant disturbance in the growth hormone (GH) /growth factor system, it occures as a result of various hereditary or acquired causes and is characterized, first of all, by a significant delay in the child's growth and physical development. GHD can be isolated or combined with deficiency of other adenohypophysis hormones. The presence of a relationship between the GH /growth factor system and vitamin D (vit D) determines the involvement of genetic changes in the vit D receptor (VDR) in the pathogenesis of GHD. Purpose - to assess the risk of developing GHD based on the investigation of the distribution of allele frequencies and genotypes of the polymorphic locus rs1544410 BsmI of the VDR gene. Materials and methods. The determination of VDR BsmI gene (rs1544410) polymorphism was performed using the polymerase chain reaction method, followed by analysis of the length of restriction fragments upon their detection by agarose gel electrophoresis in 22 prepubertal children with GHD. The serum 25-hydroxycalciferol (25(OH)D) level was determined by immunochemiluminescent method on microparticles (Abbott, USA). Results. G/A allele was most often found in children with isolated GHD and multiple pituitary insufficiency (MPH) (43.8% and 83.3%, respectively). In the presence of G/A and G/G genotypes, the risk of GHD is reliably high: OR=3.60 (95% CI 1.40-9.23); OR=10.69 (95% CI 2.34-48.85) respectively; with the A/A genotype variant the risk of GHD is reliably low OR=0.11 (95% CI 0.04-0.33). Carrying the G allele of the polymorphic locus rs1544410 Bsm I of the VDR gene is associated with the risk of developing GHD OR=5.58 (95% CI 4.51-6.90; p&lt;0.001). A significantly difference in the peak GH release was established in patients carrying the G/G and A/A, G/G and G/A alleles. 83.33% of children with MPH and 68.49% with isolated GHD had hypovitaminosis D. Vit D deficiency was recorded in carriers of all three types of alleles. Conclusions. In the presence of G/A and G/G genotypes, the risk of GHD increases, in the presence of the A/A genotype, it decreases. The G allele carrier of the polymorphic locus rs1544410 Bsm I of the VDR gene is associated with the risk of developing GHD OR=5.58 (95% CI 4.51-6.90; p&lt;0.001), despite the ideal distribution of genotypes. The research was carried out in accordance with the principles of the Helsinki Declaration. The study protocol was approved by the Local Ethics Committee of all participating institutions. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors.

Roasted Soybeans and an Estrogenic Growth Promoter Affect Growth Hormone Status and Performance of Beef Steers

This study investigated the effects of a roasted soybean (RSB)-supplemented diet and an estrogen implant (SYN; Synovex-S® ear implant, 20 mg estradiol benzoate plus 200 mg progesterone) in young crossbred beef steers on their performance and plasma growth hormone (GH) response to challenge injections of thyrotropin-releasing hormone (TRH) + GH-releasing hormone (GHRH). Twenty individually fed steers (body weight 255 ± 5 kg) were assigned to the following treatments: 1) no SYN and fed a soybean meal-supplemented diet, 2) no SYN and fed the RSB-supplemented diet, 3) plus SYN and soybean meal, and 4) plus SYN and RSB. Steers were fed 1.13 MJ metabolizable energy/kg metabolic body weight daily of an 18% protein diet. After a 5-wk growth period, all steers were challenged (intravenous injection) over a 3-wk period with three levels of a combination of TRH + GHRH (0.1 + 0.01, 1.0 + 0.1, 2.5 + 0.25 µg/kg body weight, respectively). After an additional 3 wk, steers were reimplanted and a second 5-wk growth period was followed by a single challenge of the 1.0 + 0.1 TRH + GHRH dose level. Plasma nonesterified fatty acid concentration was greater when steers were fed the RSB compared with soybean meal (265 vs. 205 µmol/L; P < 0.01; SEM = 9.5). Body weight gains for treatments 1, 2, 3 and 4 were 1.35, 1.21, 1.47 and 1.38 kg/d, respectively (RSB, P < 0.10; SYN, P < 0.07; SEM = 0.06). Gain/dry matter intake (g/kg) means were 184, 167, 197 and 184 (RSB, P < 0.04; SYN, P < 0.07; SEM = 7.5). Feeding roasted soybeans resulted in depressed area under the GH response curve [907, 555, 827 and 989 µg/(L*min) (SYN × RSB, P < 0.03; SEM = 117)] and depressed peak response (37.2, 26.6, 33.5 and 41.1 µg/L [SYN × RSB, P < 0.05; SEM = 4.5]), an effect alleviated by estrogen for young growing steers (Period 1) but not for heavier steers (Period 2).

Photoperiod-driven concurrent changes in hypothalamic and brainstem transcription of sleep and immune genes in migratory redheaded bunting.

The molecular regulation of sleep in avian migrants is still obscure. We thus investigated this in migratory redheaded buntings, where four life-history states (LHS; i.e. non-migratory, pre-migratory, migratory and refractory states) were induced. There was increased night-time activity (i.e. Zugunruhe) during the migratory state with reduced daytime activity. The recordings of the sleep-wake cycle in buntings showed increased night-time active wakefulness coupled with drastically reduced front and back sleep during migratory phase. Interestingly, we found the buntings to feed and drink even after lights-off during migration. Gene expression studies revealed increased hypothalamic expression of glucocorticoid receptor (nr3c1), and pro-inflammatory cytokines (il1b and il6) in pre-migratory and migratory states, respectively, whereas in brainstem Ca2+/calmodulin-dependent protein kinase 2 (camk2) was upregulated during the migratory state. This suggested a heightened pro-inflammatory state during migration which is a feature of chronic sleep loss, and a possible role of Ca2+ signalling in promoting wakefulness. In both the hypothalamus and brainstem, the expression of melatonin receptors (mel1a and mel1b) was increased in the pre-migratory state, and growth hormone-releasing hormone (ghrh, known to induce sleep) was reduced during the migratory state. The current results demonstrate key molecules involved in the regulation of sleep-wake cycle across LHS in migratory songbirds.

Silica-collagen nanoformulations with extended human growth hormone release

Growth hormone deficiency has been treated by the daily administration of recombinant human growth hormone (hGH) for decades. Patient compliance to this treatment is generally incomplete due to challenges including dose frequency and lack of perceived benefits. This stimulates the research on new formulations to reduce the number of periodic administrations. In this study silica nanoparticles and silica-collagen nanocomposites were evaluated for hGH loading and release. Bare nanoparticles showed higher hGH adsorption capacity than thiol- and isobutyl-bearing particles of similar diameters. Monitoring of bound protein conformation changes indicated hGH structure retention when adsorbed on bare silica nanoparticles and suggested no alterations on protein activity. Protein-loaded particles incorporated into collagen matrices (silica-collagen nanocomposites) showed a progressive protein release profile different from the observed for hGH-loaded silica nanoparticles and hGH-loaded collagen matrices. While both the collagen and the silica nanoparticle systems reached a 100 % release after 4 and 7 days respectively, silica-collagen nanocomposites showed a bi-phasic prolonged hGH release reaching approximately an 80 % after 15 days. These findings suggest that biocompatible silica-collagen nanocomposites could be used as vehicles for the prolonged delivery of hGH which could lead to a potential reduction in the number of periodic administrations.

Growth hormone-releasing hormone agonist attenuates vascular calcification in diabetic db/db mice.

Vascular calcification (VC) is an independent risk factor for cardiovascular diseases. VC increases mortality of all-causes. VC is one of most common cardiovascular complications in type II diabetes. So far, no therapy has been proven to be effective in treatment of clinical VC. The present study investigated the therapeutic effects of MR409, an agonistic analog of growth hormone-releasing hormone (GHRH-A), on VC in diabetic db/db mice. Diabetic mice were injected with MR409 subcutaneously every day for 8 weeks. Long-term treatment with MR409 improved serum lipid profile and endothelium-dependent relaxation to acetylcholine, and reduced vascular structural injury in diabetic mice without affecting serum growth hormone level. Echocardiography showed that calcium plaques present in heart valve of diabetic mice disappeared in diabetic mice after treatment with MR409. MR409 inhibited vascular calcium deposition associated with a marked reduction in the expressions of osteogenic-regulated alkaline phosphatase (ALP) and transcription osteogenic marker gene Runx2 in diabetic mice. MR409 also inhibited vascular reactive oxygen species (ROS) generation and upregulated the expressions of anti-calcifying protein Klotho in diabetic mice. Our results demonstrate that GHRH-A MR409 can effectively attenuate VC and heart valve calcification, and protect against endothelial dysfunction and vascular injury in diabetic mice without significantly affecting pituitary-growth hormone axis. The mechanisms may involve upregulation of anti-calcifying protein Klotho and reduction in vascular ROS and the expression of redox sensitive osteogenic genes Runx2 and ALP. GHRH-A may represent a new pharmacological strategy for treatment of VC and diabetics associated cardiovascular complications.

Agonist of growth hormone-releasing hormone improves the disease features of spinal muscular atrophy mice

Spinal muscular atrophy (SMA) is a severe autosomal recessive neuromuscular disease affecting children and young adults, caused by mutations of the survival motor neuron 1 gene (SMN1). SMA is characterized by the degeneration of spinal alpha motor neurons (αMNs), associated with muscle paralysis and atrophy, as well as other peripheral alterations. Both growth hormone-releasing hormone (GHRH) and its potent agonistic analog, MR-409, exert protective effects on muscle atrophy, cardiomyopathies, ischemic stroke, and inflammation. In this study, we aimed to assess the protective role of MR-409 in SMNΔ7 mice, a widely used model of SMA. Daily subcutaneous treatment with MR-409 (1 or 2 mg/kg), from postnatal day 2 (P2) to euthanization (P12), increased body weight and improved motor behavior in SMA mice, particularly at the highest dose tested. In addition, MR-409 reduced atrophy and ameliorated trophism in quadriceps and gastrocnemius muscles, as determined by an increase in fiber size, as well as upregulation of myogenic genes and inhibition of proteolytic pathways. MR-409 also promoted the maturation of neuromuscular junctions, by reducing multi-innervated endplates and increasing those mono-innervated. Finally, treatment with MR-409 delayed αMN death and blunted neuroinflammation in the spinal cord of SMA mice. In conclusion, the present study demonstrates that MR-409 has protective effects in SMNΔ7 mice, suggesting that GHRH agonists are promising agents for the treatment of SMA, possibly in combination with SMN-dependent strategies.

Growth hormone stimulates lipolysis in mice but not in adipose tissue or adipocyte culture.

The inhibitory effect of growth hormone (GH) on adipose tissue growth and the stimulatory effect of GH on lipolysis are well known, but the mechanisms underlying these effects are not completely understood. In this study, we revisited the effects of GH on adipose tissue growth and lipolysis in the lit/lit mouse model. The lit/lit mice are GH deficient because of a mutation in the GH releasing hormone receptor gene. We found that the lit/lit mice had more subcutaneous fat and larger adipocytes than their heterozygous lit/+ littermates and that these differences were partially reversed by 4-week GH injection. We also found that GH injection to the lit/lit mice caused the mature adipose tissue and adipocytes to reduce in size. These results demonstrate that GH inhibits adipose tissue growth at least in part by stimulating lipolysis. To determine the mechanism by which GH stimulates lipolysis, we cultured adipose tissue explants and adipocytes derived from lit/lit mice with GH and/or isoproterenol, an agonist of the beta-adrenergic receptors. These experiments showed that whereas isoproterenol, expectedly, stimulated potent lipolysis, GH, surprisingly, had no effect on basal lipolysis or isoproterenol-induced lipolysis in adipose tissue explants or adipocytes. We also found that both isoproterenol-induced lipolysis and phosphorylation of hormone-sensitive lipase were not different between lit/lit and lit/+ mice. Taken together, these results support the conclusion that GH has lipolytic effect in mice but argue against the notion that GH stimulates lipolysis by directly acting on adipocytes or by enhancing β-adrenergic receptors-mediated lipolysis.

Signaling mechanism of growth hormone-releasing hormone receptor.

The hypothalamic peptide growth hormone-releasing hormone (GHRH) stimulates the secretion of growth hormone (GH) from the pituitary through binding and activation of the pituitary type of GHRH receptor (GHRH-R), which belongs to the family of G protein-coupled receptors with seven potential membrane-spanning domains. Splice variants of GHRH-Rs (SV) in human tumors and other extra pituitary tissues were identified and their cDNA was sequenced. Among the SVs, splice variant 1 (SV1) possesses the greatest similarity to the full-length GHRH-R and remains functional by eliciting cAMP signaling and mitogenic activity upon GHRH stimulation. A large body of work have evaluated potential clinical applications of agonists and antagonists of GHRH in diverse fields, including endocrinology, oncology, cardiology, diabetes, obesity, metabolic dysfunctions, Alzheimer's disease, ophthalmology, wound healing and other applications. In this chapter, we briefly review the expression and potential function of GHRH-Rs and their SVs in various tissues and also elucidate and summarize the activation, molecular mechanism and signalization pathways of these receptors. Therapeutic applications of GHRH analogs are also discussed.

Vrednosti kalcitonina u pseudohipoparatiroidizmu

Pseudohypoparathyroidism type 1A is a rare endocrine disorder caused by GNAS mutation and the resulting hormone resistance at the receptor level, i.e. the activation of the intracellular pathway of the Gs alpha subunit is not possible. This disorder is most often characterized by resistance to the parathyroid hormone. However, it can also be characterized by resistance to other hormones, such as thyroid-stimulating hormone, gonadotropins (luteinizing and follicle-stimulating hormones), growth hormone-releasing hormone, and calcitonin. In this article, we describe the case of a patient diagnosed with pseudohypoparathyroidism based on phenotypic features of hereditary Albright osteodystrophy. Due to the progressive decline in intellectual functions and changing behavior, neurological examination confirmed calcifications of the CNS as part of Fahr's syndrome. During hospitalization, higher levels of thyroid-stimulating hormone and calcitonin were observed, probably as a result of resistance at the level of the receptor and its intracellular pathway. Hypercalcitoninemia occurs sporadically in cases involving pseudohypoparathyroidism type 1-a and type 1-b. Elevated levels of calcitonin should be evaluated by means of anamnesis and clinical examination involving morphological and functional tests, considering that a highly specific tumor is a marker of medullary carcinoma of the thyroid gland, as well as some neuroendocrine tumors. Some authors recommend fine needle aspiration biopsy in order to minimize the risk of medullary thyroid cancer.

Fluctuation of CD9/SOX2-positive cell populations during the turnover of GH- and TSH-producing cells in the adult anterior pituitary gland.

The adenohypophysis is comprised of the anterior and intermediate lobes (AL and IL, respectively). Cluster of differentiation 9 (CD9)- and sex-determining region Y-box 2 (SOX2)-positive cells are stem/progenitor hormone-producing cells in the AL. They are located in the marginal cell layer (MCL) facing Rathke's cleft between the AL and IL (primary niche) and the parenchyma of the AL (secondary niche). We previously showed that, in rats, CD9/SOX2-positive cells in the IL side of the MCL (IL-side MCL) migrate to the AL side (AL-side MCL) and differentiate into prolactin-producing cells (PRL cells) in the AL parenchyma during pregnancy, lactation, and diethylstilbestrol treatment, all of which increase PRL cell turnover. This study examined the changes in CD9/SOX2-positive stem/progenitor cell niches and their proportions by manipulating the turnover of growth hormone (GH)- and thyroid-stimulating hormone (TSH)-producing cells (GH and TSH cells, respectively), which are Pit1 lineage cells, as well as PRL cells. After induction, the isolated CD9/SOX2-positive cells from the IL-side MCL formed spheres and differentiated into GH and TSH cells. We also observed an increased GH cell proportion upon treatment with GH-releasing hormone and recovery from continuous stress and an increased TSH cell proportion upon propylthiouracil treatment, concomitant with alterations in the proportion of CD9/SOX2-positive cells in the primary and secondary niches. These findings suggest that CD9/SOX2-positive cells have the potential to supply GH and TSH when an increase in GH and TSH cell populations is required in the adult pituitary gland.

Actively separated microneedle patch for sustained-release of growth hormone to treat growth hormone deficiency

Growth hormone deficiency (GHD) has become a serious healthcare burden, and presents a huge impact on the physical and mental health of patients. Here, we developed an actively separated microneedle patch (PAA/NaHCO3-Silk MN) based on silk protein for sustained release of recombinant human growth hormone (rhGH). Silk protein, as a friendly carrier material for proteins, could be constructed in mild full-water conditions and ensure the activity of rhGH. After manually pressing PAA/NaHCO3-Silk MN patch to skin for 1min, active separation is achieved by absorbing the interstitial fluid (ISF) to trigger HCO3 ‒ in the active backing layer to produce carbon dioxide gas (CO2). In rats, the MN patch could maintain the sustained release of rhGH for more than 7 days, and produce similar effects as daily subcutaneous (S.C.) injections of rhGH in promoting height and weight with well tolerated. Moreover, the PAA/NaHCO3-Silk MN patch with the potential of painless self-administration, does not require cold chain transportation and storage possess great economic benefits. Overall, the PAA/NaHCO3-Silk MN patch can significantly improve patient compliance and increase the availability of drugs, meet current unmet clinical needs, improve clinical treatment effects of GHD patients.

L-Serine Influences Epigenetic Modifications to Improve Cognition and Behaviors in Growth Hormone-Releasing Hormone Knockout Mice.

Neurodegenerative diseases feature changes in cognition, and anxiety-like and autism-like behaviors, which are associated with epigenetic alterations such as DNA methylation and histone modifications. The amino acid L-serine has been shown to have beneficial effects on neurological symptoms. Here, we found that growth hormone-releasing hormone knockout (GHRH-KO) mice, a GH-deficiency mouse model characterized by extended lifespan and enhanced insulin sensitivity, showed a lower anxiety symptom and impairment of short-term object recognition memory and autism-like behaviors. Interestingly, L-serine administration exerted anxiolytic effects in mice and ameliorated the behavioral deficits in GHRH-KO. L-serine treatment upregulated histone epigenetic markers of H3K4me, H3K9ac, H3K14ac and H3K18ac in the hippocampus and H3K4me in the cerebral cortex in both GHRH-KO mice and wild type controls. L-serine-modulated epigenetic marker changes, in turn, were found to regulate mRNA expression of BDNF, grm3, foxp1, shank3, auts2 and marcksl1, which are involved in anxiety-, cognitive- and autism-like behaviors. Our study provides a novel insight into the beneficial effects of L-serine intervention on neuropsychological impairments.

Towards a robust test to detect gene doping for anabolic enhancement in human athletes.

Success in gene therapy in treating human disease makes this technology attractive to enhance athletic performance, creating the need for gene doping detection. In 2021, World Anti-Doping Agency (WADA) approved the first gene doping test. Here, we describe a new method to detect doping with four additional genes, follistatin, growth hormone 1, growth hormone-releasing hormone and insulin-like growth factor 1, that may improve performance by increasing muscle size and strength. The method utilises four hydrolysis probe-based polymerase chain reaction (PCR) assays that target the transgenes based on the coding sequence of the four endogenous genes. The assays are specific, reproducible and capable to detect five copies of transgene in the presence of very similar endogenous gene in 25,000 times excess. To underpin reliable and comparable routine method performance by doping testing laboratories, a synthetic reference material for the method was designed and generated following the ISO Guide 35. The complete method was validated in blood samples using plasma as extraction matrix and QIAamp DNA blood midi DNA extraction kit. All blood samples from different donors (n = 8) simulated to be negative or positive (1500 transgene copies spiked per millilitre of blood) for the transgenes were reported correctly. The new method that targets four additional genes will extend the capabilities of laboratories involved in doping control to protect athletes' health, fairness and equality.

Discovery of Paltusotine (CRN00808), a Potent, Selective, and Orally Bioavailable Non-peptide SST2 Agonist.

The discovery of a novel 4-(4-aminopiperidinyl)-3,6-diarylquinoline series of potent SST2 agonists is described. This class of molecules exhibit excellent selectivity over SST1, SST3, SST4, and SST5 receptors. The compound 3-[4-(4-aminopiperidin-1-yl)-3-(3,5-difluorophenyl)quinolin-6-yl]-2-hydroxybenzonitrile (22, paltusotine, formerly known as CRN00808) showed no direct inhibition of major cytochrome P450 enzymes or the hERG ion channel and had sufficient exposure in rats and excellent exposure in dogs upon oral dosing. In pharmacodynamic studies, compound 22 dose-dependently suppressed growth hormone (GH) secretion induced by an exogenous growth-hormone-releasing hormone (GHRH) challenge in both male and female rats following a single oral dose and suppressed IGF-1 levels with repeated oral administration in both rats and dogs. To the best of our knowledge, compound 22 is the first non-peptide SST2 agonist to advance to human clinical trials and is currently in Phase 3 trials in acromegaly patients and a Phase 2 trial in neuroendocrine tumor patients suffering from carcinoid syndrome.

Growth Hormone-Releasing Hormone Antagonist JV-1-36 Suppresses Reactive Oxygen Species Generation in A549 Lung Cancer Cells.

Growth hormone-releasing hormone (GHRH) and its receptors are expressed in a variety of human cancers, and have been involved in malignancies. GHRH antagonists (GHRHAnt) were developed to suppress tumor progression and metastasis. Previous studies demonstrate the involvement of reactive oxygen species (ROS) in cancer progression. Herein, we investigate the effect of a commercially available GHRH antagonist, namely JV-1-36, in the redox status of the A549 human cancer cell line. Our results suggest that this peptide significantly reduces ROS production in those cells in a time-dependent manner and counteracts H2O2-induced ROS. Our study supports the anti-oxidative effects of JV-1-36 and contributes in our knowledge towards the in vitro effects of GHRHAnt in cancers.

Effect of tesamorelin in people with HIV with and without dorsocervical fat: Post hoc analysis of phase III double-blind placebo-controlled trial.

Tesamorelin, a synthetic growth hormone-releasing hormone, is indicated for the reduction of visceral adipose tissue (VAT) in people with HIV. Here, we performed a post hoc analysis of participants receiving tesamorelin for 26 weeks in a phase III clinical trial. Efficacy data were compared between individuals with and without dorsocervical fat, stratified by tesamorelin response. Among tesamorelin responders, VAT and waist circumference (WC) decreased in both dorsocervical fat groups and did not statistically differ (VAT P = 0.657, WC P = 0.093). These data demonstrate that tesamorelin is equally effective and should be considered in the treatment of excess VAT regardless of the presence of dorsocervical fat.

Treatment optimization of the age-related cardiovascular and neurological pathology using known metabolic, cytoprotective, vasodilatory action substances. Review

Stressful situations that accompany us during military operations provoke a significant increase in the incidence of cardiovascular and psychoneurological pathology, especially among the elderly. Therefore, there is a need for a complex approach to treatment, in particular, with the use of combined drugs. The review presents data from preclinical and clinical studies on drugs with metabolic action - meldonium (trimethylhydrazinium propionate), L-arginine, and inosine. It has been shown that, apart from the general pharmacotherapeutic action, these drugs have a significant clinical effect on various illnesses in the form of adjunctive therapy. Antioxidant, neuroprotective, vasodilatory, and several pleiotropic effects of meldonium have been established. The use of meldonium as part of combined therapy improves the prognosis in cardiovascular and neurological disease treatment. Most reports ascribe the clinical benefits of L-arginine in cardiovascular diseases to the provision of NO. L-arginine is the only precursor for the NO-synthase reaction. NO is produced by all tissues of the body and plays particularly important roles in cardiovascular homeostasis. Very few articles examine the effects of L-arginine supplementation on central nervous system (CNS) function. However, accumulating evidence indicates that NO plays a role in memory formation. The possible role of L-arginine in Alzheimer's disease was investigated, taking into account the known functions of L-arginine in atherosclerosis, redox stress and inflammation, regulation of synaptic plasticity and neurogenesis, as well as modulation of glucose metabolism and insulin activity. Evidence is provided that L-arginine may play a prominent role in protecting against age-related degenerative diseases such as Alzheimer's disease. L-arginine has been demonstrated to improve peripheral circulation, renal function, and immune function. It also possesses anti-stress and adaptogenic capabilities. L-arginine stimulates the release of growth hormone as well as the release of pancreatic insulin and glucagon and pituitary prolactin. The antioxidant property of L-arginine has been well documented in several reports. As well known that inosenhancesance the myocardial energy potential improvesrove coronary circulation. At the same time over the past two decades, inosine has been shown to evoke significant improvements in motor function and visceral organ control in preclinical models of neurologic injury including spinal cord injury, stroke, traumatic brain injury, multiple sclerosis, and Parkinson`s disease through its ability to enhance the growth of axon collaterals from undamaged neurons. The basis of these beneficial effects stems from its antioxidant, anti-inflammatory, anxiogenic and neuroprotective properties. Keywords: age-related pathology; combined drugs; meldonium; L-arginine; inosine, endothelial dysfunction.

Growth Hormone Response to L-Arginine Alone and Combined with Different Doses of Growth Hormone-Releasing Hormone: A Systematic Review and Meta-Analysis.

Arginine (ARG) can modulate growth hormone (GH) release by suppressing its endogenous inhibitory regulator, somatostatin. ARG also induces the release of the GH-releasing hormone (GHRH). This study aims to review the effects of L-arginine supplementation alone and combined with GHRH in different doses on GH secretion. In this systematic review and meta-analysis, an electronic literature search was conducted on Medline database (PubMed), Scopus, and Web of Science databases. All eligible studies were randomized clinical trials that reported the effects of ARG supplementation alone or with GHRH on GH levels. Mean difference (MD) and 95% confidence intervals (CI) were computed as the effect size. Meta-analyses showed significant effects of ARG alone on GH release (MD = 10.07, 95% CI: 7.87, 12.28). Moreover, the response of GH was greater with ARG in combination with GHRH (MD = 24.96, 95% CI: 17.51, 32.42). There was no significant difference between the patients and healthy individuals and between oral and injection use of ARG. The systematic review revealed the important role of ARG in combination with other amino acids on GH secretion in patients with GH deficiency. This study revealed that in GH-deficient individuals, high doses of ARG supplementation in combination with GHRH and/or other amino acids might have potential therapeutic effects on increasing GH concentrations. These findings propose that ARG supplementation can be considered as a potential stimulator in management of GH deficiency.