Administration Of Analogue Research Articles

Altered biodistribution of [68Ga]Ga-DOTA-TOC during somatostatin analogue treatment.

The need for an interval between the administration of long-acting Somatostatin Receptor Analogues (SSA) and the [68Ga]Ga-DOTA-TATE PET has been questioned based on recent literature in the new EANM guidelines. Here an earlier studies showed that SSA injection immediately before SSTR PET had minimal effect on normal organ and tumor uptake (1). However, data are scarce and there are (small) differences between [68Ga]Ga-DOTA-TATE and [68Ga]Ga-DOTA-TOC binding affinity, and it remains unknown whether these findings can be directly translated to scans with [68Ga]Ga-DOTA-TOC as well. The purpose of this study was to assess the effect of SSA use on the biodistribution in a subsequent [68Ga]Ga-DOTA-TOC PET/CT and compare this intra-individually across several cycles of SSA treatments. Retrospectively, 35 patients with NENs were included. [68Ga]Ga-DOTA-TOC PET at staging and after the 1st and 2nd cycle of SSA were included. SUVmean and SUVmax of blood, visceral organs, primary tumor and two metastases were determined. Also, the interval between SSA therapy and the PET scan was registered. Treatment with SSA resulted in a significantly higher bloodpool activity and lower visceral tracer uptake. This effect was maintained after a 2nd cycle of SSA therapy. Furthermore, there was an inverse relationship between bloodpool tracer availability and visceral tracer binding and a positive correlation between bloodpool tracer availability and primary tumor tracer uptake. With an interval of up to 5days, there was a significantly higher bloodpool activity than at longer intervals. Absolute comparison of the SUV on [68Ga]Ga-DOTA-TOC PET should be done with caution as the altered biodistribution of the tracer after SSA treatment should be taken into account. We recommend not to perform a scan within the first 5days after the injection of lanreotide.

Comparative effectiveness of different methods of using the analogue of gonadotropin-releasing hormone for ovulation stimulation in rabbit does

Modern reproductive technologies require artificial insemination (AI) protocols that are safe for the health of animals and do not violate their welfare. Stress factors arising in the reproduction process of industrial rabbit breeding negatively affect the sexual function and reproductive performance of rabbits and their offspring. In recent years, researchers have focused on alternative methods of ovulation stimulation, including intravaginal introduction of hormonal means of its induction. Therefore, the aim of our study was a comparative evaluation of the effectiveness of the intramuscular method of administration of the gonadotropin-releasing control (GnRH) analogue and its addition to the sperm dose for AI on Hyplus rabbit (n = 30), which were randomly divided into three groups. For this, buserelin acetate was administered intramuscularly at a dose of 1 μg per rabbit immediately after artificial insemination (control group). Experimental animals were inseminated with sperm doses with the addition of a GnRH analogue in the amount of 25 μg (experimental group 1) and 15 μg (experimental group 2). The influence of the method of administration of GnRH analogue on reproductive function was evaluated by indicators of the effectiveness of AI, fertility, and the dynamics of the progesterone level during pregnancy. A decrease in fecundity was observed in females; for example, in experimental group 1, the effectiveness of AI in terms of the number of rabbits was 64.3 %; in animals of experimental group 2 – 41.2 %, and the number of inseminations in this group of rabbits was 41.7% higher compared to control data. The fertility of rabbits of all groups was high, reaching the maximum value in the control group (10.42 ± 0.52 heads/female). Fertility according to live newborns in experimental group 1 was the highest among all groups of rabbits and was 9.67 ± 0.49 heads/female, which showed an increasing trend compared to the control. Also, in the animals of experimental group 1, an increase in the level of progesterone in blood serum was observed (on the 7th day of pregnancy by 13.2 %, on the 14th day by 14.3 %, on the 21st day by 16.4 %). In contrast, in experimental group 2, a significant decrease in the progesterone level was noted. Thus, 25 μg of GnRH analogue added to the extender is optimal. It is worth noting that there were no advantages of intravaginal administration over intramuscular administration in terms of reproductive performance. However, the number of live births and progesterone levels were improved.

Adrenocortical hemorrhage following intravenous tetracosactide in a dog with hypercortisolism.

To summarize findings from a case of adrenocortical hemorrhage following tetracosactide injection during ACTH stimulation testing for monitoring of trilostane therapy in a dog. A 12-year old neutered male dog with adrenal-dependent hypercortisolism. 4 hours after ACTH stimulation testing, the patient developed vomiting, lethargy, and abdominal pain. Abdominal ultrasound was performed before and after an ACTH stimulation test. Following ACTH stimulation testing, there was progressive bilateral adrenal enlargement and free abdominal fluid had developed. This was considered to be caused by adrenocortical inflammation and hemorrhage secondary to the synthetic ACTH analog, tetracosactide, used during stimulation testing. A resting cortisol performed 5 hours after tetracosactide injection was not consistent with iatrogenic hypoadrenocorticism. The patient was managed with analgesia, IV fluids, and corticosteroids and made a full recovery. To the authors' knowledge, this was the first reported case of adrenocortical hemorrhage following administration of a synthetic ACTH analog in a dog. This should be considered as a rare potential complication of ACTH stimulation testing.

Progestin-primed ovarian stimulation.

The use of progestins as pituitary suppressors has increased progressively, along with more detailed indications for their use, thereby consolidating an alternative approach to the personalization of ovarian stimulation. Based on the ability of progesterone to inhibit ovulation, progestins have been used in ovarian stimulation (OS) follicular protocols to prevent a luteinizing hormone surge in patients undergoing in vitro fertilization (IVF), as an alternative to gonadotropin-releasing hormone (GnRH) analogue administration. This review explores the different types of progestogen protocols and their efficacy depending on the type of population or reproductive procedure in which they are administered and in comparison with that of GnRH analogues. Their effect on oocytes and embryos and their safety and cost-effectiveness are also analyzed. Progestins have proven their effectiveness as a gonadotropin adjuvant in terms of ovarian response, reproductive outcome, and safety. In addition, they offer the convenience of oral administration and a lower cost than GnRH analogues. Whereas oocytes or embryos should be vitrified as it displaces the receptive period with the consequent asynchrony between embryo and endometrium. The evidence endorses progestins as a more friendly approach to OS, especially when frozen-thawed embryo transfer is planned.

The effect of gonadoliberin analog treatment in precocious puberty on polycystic ovarian syndrome prevalence in adulthood.

The study group consists of 24 women (median age 22 88 years, median BMI 23.5) treated with GnRHa for central precocious puberty in childhood. The control group includes 40 women (median age 23 years, median BMI 25.6) diagnosed with isolated premature thelarche and not using GnRHa in the childhood. Anthropometric measurements, ultrasound examination of minor pelvis and hormonal profile were performed. PCOS diagnosis was based on Rotterdam criteria. The study confirmed a higher prevalence of PCOS in the study group (50%) than in the control group (10%); p=0.0006. Significant, linear correlation between free testosterone levels and ovarian size was found in the study group (R=0.45 p= 0.03). GnRHa therapy during childhood may have a potential influence on incidence of PCOS in the adulthood. Therefore, in this group of patients long-term follow-up focused on screening for PCOS would seem beneficial.

Association between blood hormones and fecundity in rabbit does

The aim of the present study was to examine the association between blood hormone level and fecundity in rabbit does. The ovulation of nulliparous New Zealand White rabbits was induced by administration of PMSG and LH-RH analogue. Next day, the does were inseminated, blood was collected and the plasma levels of IGFI, leptin, progesterone and estradiol were measured by radioimmunoassay. After the birth of pups, the retrospective comparison of level of hormones in the blood of fertile and non-fertile animals was performed. Fertile does had significantly higher blood level of IGF-I and lower concentration of leptin than the infertile ones. No significant differences in blood progesterone and estradiol level was found between fertile and non-fertile females. These observations suggest that blood IGF-I and leptin level could be useful for diagnostics and prediction of rabbit does' fecundity.

Efeito do tratamento com gonadotrofina na transferência de embriões nos resultados de prenhez em bovinos

Abstract The objectives were to evaluate the effects of recipient category, season and administration of a gonadorelin analogue at the time of fixed-time embryo transfer (FTET) on pregnancy per FTET at 30 and 60 days after oestrus and on pregnancy losses (PL). Recipients were randomly assigned to: treated group (n = 624), in which recipients received an intramuscular injection of 0.2 mg of gonadorelin (Fertagyl®) at FTET; or a control group (n = 687) that remained untreated. Recipients were previously treated with a synchronisation protocol based on progesterone and oestradiol. All embryos were produced in vitro. The data with binomial distribution were analysed by multivariate logistic regression, using the GLIMIX procedure of SAS. Higher P/FTET was observed at 30 days (45.8 vs. 40.0%; P = 0.03) and 60 days (43.0 vs. 37.0%; P = 0.01) in the treated group. There was a tendency toward reduced PL in the treated group (4.0 vs. 7.0%; P = 0.09). Dry cows (2.70%) and lactating cows (2.47%) had less PL (P = 0.001) compared with heifers (10.42%). In the spring/summer season the P/ FTET at 60 days was smaller (P =0.024). Greater PL tended to occur in the warmer season. Treatment with gonadorelin at the time of bovine ET increased the pregnancy per ET at days 30 and 60 and reduced PL. Additionally, dry and lactating recipient cows showed a lower PL rate compared to heifers. Furthermore, ET performed in the warmer seasons of the year resulted in a lower pregnancy rate at day 60 and greater PL.

Pharmacological methods for ovarian function and fertility preservation in women with cancer: A literature review.

Oncofertility is an extremely significant topic that is increasingly being discussed owing to increased evidence indicating that fertility preservation does not affect the treatment outcomes of patients with cancer but significantly contributes to preserving life quality. The effect of chemotherapy can range from minimal effects to complete ovarian atrophy. Limited data are available on the effects of monoclonal antibodies and targeted therapies on the ovaries and fertility. Temporary ovarian suppression by administering a gonadotropin-releasing hormone agonist (GnRHa) during chemotherapy decreases the gonadotoxic effect of chemotherapy, thereby diminishing the chance of developing premature ovarian insufficiency (POI). At present, the concomitant administration of GnRH analogs during chemotherapy is the only accepted pharmacological method for preserving ovarian function. Notably, most randomized studies on the effectiveness of luteinizing hormone-releasing hormone agonists during chemotherapy in preventing POI have been conducted in women with breast cancer, with a considerably small number of studies on patients with hematological malignancies. Furthermore, most randomized controlled trials on breast cancer have revealed a decrease in treatment-induced POI risk, regardless of the hormone receptor status. In addition, studies on hematological malignancies have yielded negative results; nevertheless, the findings must be interpreted with caution owing to numerous limitations. Current guidelines from the American Society of Clinical Oncology and ESMO Clinical Practice Guidelines recommend sperm, oocyte, and embryo cryopreservation as a standard practice and only offering GnRHa to patients when proven fertility preservation methods are not feasible. In this manuscript, we present a comprehensive literature overview on the application of ovarian suppression with GnRHa during chemotherapy in patients with cancer by addressing preclinical and clinical data, as well as future perspectives in this field that upcoming research should focus on.

Reactive changes of kisspeptin-producing hypothalamic neuroendocrine cells during hypogonadism and its replacement therapy by the kisspeptin analogue in rats

BACKGROUND: This study is devoted to the morphological substantiation of the model of male hypogonadism and to establishing the effectiveness of its replacement therapy at the level of the central link of the hypothalamic-pituitary-testicular axis using morphological methods. Information about reactive changes in neuroendocrine cells that synthesize the peptide kisspeptin, which regulates the production of gonadoliberin when modeling male and female hypogonadism, has not been described in the literature, which prevents the creation of a micro-morphological basis for the development of models of hypogonadism and the implementation of further preclinical studies of the effectiveness of its replacement therapy. The goal is to carry out a morphological analysis of kisspeptin-producing neuroendocrine cells of the hypothalamus in normal conditions, with experimental hypogonadism and after replacement therapy. AIM: To carry out a morphological analysis of kisspeptin-producing neuroendocrine cells of the hypothalamus in normal conditions, with experimental hypogonadism and after replacement therapy. MATERIALS AND METHODS: The objects of the study were 3 groups of adult male Wistar rats 6–8 months of age. In animals of the first and second groups, after anesthesia, total ischemia of both testicles was caused by ligating the left and right spermatic cord with the vascular bundle of the testicle for 60 minutes. Rats of the second group, a few minutes after restoration of testicular blood flow, were given replacement therapy by daily administration of a synthetic analogue of kisspeptin KS6 for 7 days. Control animals of the third group were subjected to sham surgery. After 10 days, all animals were sacrificed, their brains were removed and embedded in paraffin. Nissl-stained frontal histological sections of the most massive areas of the kisspeptin-producing nuclei of the hypothalamus-periventricular and arcuate-were examined using the Imagescope program (Electronic Analysis, Russia). The number of cell bodies of viable and dead neurons was counted (under the control of immunohistochemical identification of the caspase-3 antigen), and the area of the body, nucleus and cytoplasm of viable cells was calculated. Statistical processing of the data was carried out using the GraphPad PRISM (USA) program to determine the median, upper and lower quartiles. Differences were considered significant at p 0.01. RESULTS: Simulation of acute ischemia caused a significant increase in the number of dead neurons, a slight decrease in the number of viable neurons and a decrease in the area of their cytoplasm in both kisspeptin-producing nuclei. As a result of KS6 replacement therapy, most neuronal cell bodies retained their original phenotype, but the number of dead neurons was high in both experimental groups. CONCLUSIONS: Modeling of male hypogonadism using the method of bilateral acute testicular ischemia induces death and partially reversible degenerative changes in kisspeptin-producing neuroendocrine cells of the hypothalamus. Neuropeptide KS6 has a pronounced restorative effect on kisspeptin-producing neurons of the hypothalamus, which is due to its specific activating effect on endocrine cells of all parts of the hypothalamic-pituitary-testicular axis.

Circadian Rhythms Metabolically Regulate Bone Marrow Retained Primitive Hematopoietic Stem Cell Size and Function

Most primitive hematopoietic stem cells (pHSC; LSK SLAM CD34 - EPCR +) are bone marrow (BM) retained in a quiescent non motile state, and are the only chemotherapy resistant HSC which requires their rapid exit from homeostatic quiescence on demand to prevent lethal hematology failure. Circadian rhythms induce daily release of progenitor cells and low levels of rarely cycling pHSCs to replenish the blood and lymphatics with new maturing cells. Metabolically, pHSCs are characterized by their dependence on glycolysis, with low mitochondrial activity and membrane potential (MMP), associated with higher competitive repopulation potential. However, if their metabolism is influenced by circadian cues is currently unknown. We report here that pHSCs at night are more glycolytic with higher surface expression of the glucose transporter Glut1, and higher glucose uptake. Repeated administration of the glucose analog, 2-deoxyglucose (2-DG), during daylight mimicked the night phenotype and enhanced HSC engraftment potential. However, nocturnal administration of 2-DG did not further improve glucose uptake nor HSC engraftment potential, suggesting glycolytic saturation. To further understand these metabolic oscillations of glucose uptake, we investigated the circadian, transcriptional signatures by single pHSC RNA-seq analysis. We found higher expression of mitophagy-related genes at night. Genes regulating mitochondrial function, were also significantly down regulated at night leading to low MMP in pHSC. While mitochondrial ROS levels were higher, cytoplasmic ROS levels were significantly reduced in pHSC at night. Importantly, we further found at night, low-functioning pHSC mitochondria to also undergo higher levels of fission as assessed by increased expression of the active mitochondrial fission marker, phospho-Drp1 (S616). To better understand the molecular pathways mediating daily circadian metabolic reprogramming between glycolysis and mitochondrial activity, we monitored our gene set enrichment analysis. We found the Wnt/b-catennin and HIF-1a signaling pathways to be significantly increased at night in pHSC. Active Wnt signaling, leads to enhanced b-catenin localization to the nucleus which is enhanced by downstream effector of Wnt activation, FOXM1. We observed higher total protein expression of FOXM1 at night. While its nuclear and cytoplasmic localization were reduced, we observed significantly higher FOXM1 levels in the mitochondria. FOXM1 localization to the energy powerhouse has been shown to inhibit mitochondrial activity. Blocking mitochondrial recruitment of FOXM1 with a specific canonical Wnt inhibitor at night led to upregulation of MMP, reversing mitochondrial metabolic responses in pHSC. Finally, daily genetic changes between night Wnt, HIF-1a and glycolysis, versus daylight GSK3b, m-TOR signaling and enhanced mitochondrial activity in BM retained pHSC, also led to cell size changes. We documented reduced quiescent pHSC size at night associated with their increased BM maintenance and higher repopulation potential. While larger sized pHSCs in the morning during the time of blood replenishment, increased their migration and development potential, for their rapid exit from quiescence on demand. Our study reveals daily circadian cues dynamically determine Wnt-mediated FOXM1 bidirectional shuttling between the nucleus and the mitochondria, leading to metabolic switching of pHSCs to maintain their cellular fitness. Our data define key signaling pathways controlling pHSC quiescence and diverse circadian metabolic activities for accumulated ROS and old mitochondria clearance and turnover, keeping them ready for rapid activation in alarm situations.

Thyrotropin-secreting pituitary adenomas: clinical features and results of treatment in 45 patients

Thyrotropin-secreting pituitary adenomas (TSH-PA) are a rare cause of thyrotoxicosis and account for 0.5-2% of all pituitary adenomas. Taking into account the rarity of the disease, it is extremely important to analyze each case of TSH-PA. To analyze the clinical characteristics and treatment outcomes of patients with TSH-PA, as well as to determine preoperative and early postoperative factors that predict long-term remission. In a single-center retrospective study we analyzed clinical signs, laboratory and instrumental studies, as well as the treatment outcomes of patients with TSH-PA from 2010 to 2023. Preoperative factors, as well as TSH level measured on day 3 postoperatively, were evaluated for their ability to predict long-term remission when comparing groups of patients with and without remission. The study included 45 patients with TSH-PA (14 men, 31 women), with a median age of 45 years [30; 57]. The most common clinical manifestations of TSH-PA were: cardiac arrhythmia in 37 (82.2%) patients, thyroid pathology in 27 (60%), neurological disorders in 24 (53.35%). Most PAs were macroadenomas (n=35, 77.8%). Preoperatively, 28 (77.8%) patients received somatostatin analogs, and 20 (71.4%) patients were euthyroid at the time of surgery. Surgical treatment was performed in 36 (80%) patients, postoperative remission was achieved in 31 cases (86.1%). Administration of somatostatin analogues to patients with no remission/relapse after surgery lead to the remission in 100% of cases (4/4). A 1 mm increase in PA size raised the odds of recurrence/no remission by 1.15-fold,and PA invasion during surgery - by 5.129 fold. A TSH level on day 3 postoperatively above 0.391 mIU/L (AUC, 0.952; 95% CI 0.873-1.000; standard error 0.04; p<0.001) identifies patients with relapse/absence of remission after surgical treatment (sensitivity = 100%, specificity = 88.9%). The TSH-PA in the structure of PAs is extremely rare, and as a result, most of them are misdiagnosed and detected already at the stage of macroadenoma. The most effective method of treatment is transnasal transsphenoidal adenomectomy. Somatostatin analogues can be used as second-line therapy if surgical treatment is ineffective. We have proposed a possible model for postoperative TSH levels (>0.391 mU/l) to predict recurrence of TSH-PA, which requires validation on an expanded number of cases.

Oral administration of a 2-aminopyrimidine robenidine analogue (NCL195) significantly reduces Staphylococcus aureus infection and reduces Escherichia coli infection in combination with sub-inhibitory colistin concentrations in a bioluminescent mouse model.

We have previously reported promising in vivo activity of the first-generation 2-aminopyramidine robenidine analogue NCL195 against Gram-positive bacteria (GPB) when administered via the systemic route. In this study, we examined the efficacy of oral treatment with NCL195 (± low-dose colistin) in comparison to oral moxifloxacin in bioluminescent Staphylococcus aureus and Escherichia coli peritonitis-sepsis models. Four oral doses of 50 mg/kg NCL195, commencing immediately post-infection, were administered at 4 h intervals in the S. aureus peritonitis-sepsis model. We used a combination of four oral doses of 50 mg/kg NCL195 and four intraperitoneal doses of colistin at 0.125 mg/kg, 0.25 mg/kg, or 0.5 mg/kg in the E. coli peritonitis-sepsis model. Subsequently, the dose rates of four intraperitoneal doses of colistin were increased to 0.5 mg/kg, 1 mg/kg, or 2 mg/kg at 4 h intervals to treat a colistin-resistant E. coli infection. In the S. aureus infection model, oral treatment of mice with NCL195 resulted in significantly reduced S. aureus infection loads (P < 0.01) and longer survival times (P < 0.001) than vehicle-only treated mice. In the E. coli infection model, co-administration of NCL195 and graded doses of colistin resulted in a dose-dependent significant reduction in colistin-susceptible (P < 0.01) or colistin-resistant (P < 0.05) E. coli loads compared to treatment with colistin alone at similar concentrations. Our results confirm that NCL195 is a potential candidate for further preclinical development as a specific treatment for multidrug-resistant infections, either as a stand-alone antibiotic for GPB or in combination with sub-inhibitory concentrations of colistin for Gram-negative bacteria.

Latanoprost incorporates in the tear film lipid layer: An experimental and computational model study

Glaucoma is a leading cause of blindness worldwide, with elevated intraocular pressure being a major risk factor for its development and progression. First-line treatment for glaucoma relies on the administration of prostaglandin analogs, with latanoprost being the most widely used. However, before latanoprost reaches the cornea, it must pass through the tear film and tear film lipid layer (TFLL) on the ocular surface. Given the significant lipophilicity of latanoprost, we hypothesize that TFLL could, to a certain extent, act as a reservoir for latanoprost, releasing it on longer time scales, apart from the fraction being directly delivered to the cornea in a post-instillation mechanism. We investigated this possibility by studying latanoprost behavior in acellular in vitro TFLL models. Furthermore, we employed in silico molecular dynamics simulations to rationalize the experimental results and obtain molecular-level insight into the latanoprost-TFLL interactions. Our experiments demonstrated that latanoprost indeed accumulates in the TFLL models, and our simulations explain the basis of the accumulation mechanism. These results support the hypothesis that TFLL can serve as a reservoir for latanoprost, facilitating its prolonged release. This finding could have significant implications for optimizing glaucoma treatment, especially in the development of new drug delivery systems targeting the TFLL.

Advances in the Administration of Vitamin D Analogues to Support Bone Health and Treat Chronic Diseases.

Vitamin D (VD) exerts a wide variety of biological actions in addition to its well-known roles in calcium homeostasis. Nutritional VD deficiency induces rachitic abnormalities in growing children and osteomalacia in adults, and it has been proposed to underlie the onset and development of multiple non-communicable chronic diseases. Therefore, the administration of VD or synthetic VD analogues represents a promising therapeutic strategy; indeed, VD and a VD agonist have shown clinical promise in mitigating osteoporosis and symptoms of insufficient calcium intake. However, even though high doses of VD analogues have shown pre-clinical efficacy against several diseases, including cancers, they have not yet had wide-spread clinical success. This difference may be due to limitation of clinical doses in light of the inherent calcemic action of VD. An approach to overcome this problem involves the development of VD analogues with lower calcemic activity, which could be administered in high doses to attenuate the onset and progress of disease. In a similar strategy, selective estrogen receptor modulators have had success as anti-osteoporosis drugs, and they have shown benefit for other estrogen target organs by serving as partial antagonists or agonists of estrogen receptor α. It is thus conceivable to generate synthetic partial antagonists or agonists for the VD receptor (VDR) that would exert beneficial effects on bone and other VD target organs. In this review, we discuss the molecular basis of the development of such synthetic VDR ligands from the viewpoint of roles of VDR in gene regulation.

Эффективность использования региональных сырьевых ресурсов с целью повышения питательной ценности кормов

Purpose. Scientific and practical substantiation of the positive impact of the developed new feed additives on the metabolism of farm animals and poultry. Materials and Methods. The studies were carried out using traditional scientific methods of collecting information, processing primary material, generalization, and systematization. The analysis of biochemical, zootechnical, morphological, histological, organoleptic, functional and technological indicators was carried out in accordance with the generally accepted normative and technical documentation. Discussion. It has been proven that the use of natural sorbents and minerals (bentonites, diatomites, limestones, various fractions of bischofite), secondary raw materials and food production wastes (cake, meal, pomace) in the composition of feed for cattle makes it possible to reduce the technogenic load on the animal body (in 3-6 times), increase the level of conversion of feed nutrients (16-40%), improve metabolic processes, increase productivity (10-16%) and the level of profitability of the industry (7-14%). At the same time, animals of different breeds and directions of productivity differ in their ability to accumulate ecotoxicants. Inclusion in the diet of a vitamin-mineral complex containing betacarotene, vitamins E, C and selenium in a bioavailable form makes it possible to eliminate the stress factor that occurs during the parenteral administration of a commercial two-component analogue and achieve a more significant physiological effect on the body of lactating cows. The developed protein-mineral preparations containing bioavailable forms of iodine and selenium, feed additives based on lactulose in combination with honey extracts of highly valuable plant materials, biologically active complexes of lactulose and regional natural resources stimulate immune mechanisms, contribute to the formation of the functional properties of livestock products, which is especially important in the prevention of alimentary-dependent conditions in the population. Laying hens that consumed enriched feed used the nutrients of the diet more fully, as a result, more of them were excreted in egg products. So, protein with an egg was excreted more by 10.9-13.2%, fat – by 11.4-14.3%, calcium – by 2.3-2.7%, phosphorus – by 3.5-4.2%. In pig breeding, the results of the work performed have been tested and recommended for implementation in order to activate metabolic processes in the animal body, more complete protein digestion – by an average of 2.0%, an increase in the degree of nitrogen utilization – by an average of 6.0%, which leads to accumulation in the carcass of a higher protein content (on average by 19.2%). It has been established that the use of meat obtained from pigs grown with the use of feed antibiotics by rats leads to an increase in the functional activity of the liver, mainly due to the activation of protein metabolism, and the use of lard in the diet of rats causes an increase in the detoxification function of the liver, which leads to an increase in the activity of transaminases in the blood and tissue of the organ, a change in lipid metabolism and the appearance of fat-modified hepatocytes. The prospects for the use of regional entomoresources in feeding beef cattle are substantiated. As a result of studying the chemical composition and nutritional value of the extruded locust additive, its effect on the digestibility and use of dietary nutrients, the dynamics of morphological and biochemical blood parameters, the linear and weight gain of experimental calves, meat productivity, slaughter parameters of calves and the quality of raw meat, a economic efficiency of beef production, the expediency of further implementation of the development has been experimentally confirmed. Conclusion. Highly effective approaches have been developed to realize the genetic potential of regional breed resources by increasing the level of nutrient conversion of feed and diets.

Mitochondrial Peptide Humanin Facilitates Chemoresistance in Glioblastoma Cells.

Humanin (HN) is a mitochondrial-derived peptide with robust cytoprotective effects in many cell types. Although the administration of HN analogs has been proposed to treat degenerative diseases, its role in the pathogenesis of cancer is poorly understood. Here, we evaluated whether HN affects the chemosensitivity of glioblastoma (GBM) cells. We found that chemotherapy upregulated HN expression in GBM cell lines and primary cultures derived from GBM biopsies. An HN analog (HNGF6A) boosted chemoresistance, increased the migration of GBM cells and improved their capacity to induce endothelial cell migration and proliferation. Chemotherapy also upregulated FPR2 expression, an HN membrane-bound receptor, and the HNGF6A cytoprotective effects were inhibited by an FPR2 receptor antagonist (WRW4). These effects were observed in glioma cells with heterogeneous genetic backgrounds, i.e., glioma cells with wild-type (wtIDH) and mutated (mIDH) isocitrate dehydrogenase. HN silencing using a baculoviral vector that encodes for a specific shRNA for HN (BV.shHN) reduced chemoresistance, and impaired the migration and proangiogenic capacity of GBM cells. Taken together, our findings suggest that HN boosts the hallmark characteristics of GBM, i.e., chemoresistance, migration and endothelial cell proliferation. Thus, strategies that inhibit the HN/FPR2 pathway may improve the response of GBM to standard therapy.

Gonadotropins and Sex Steroid Hormones in Captive-Reared Small Yellow Croaker (Larimichthys polyactis) and Their Role in Female Reproductive Dysfunction.

The seed production of small yellow croaker (SYC) is constrained by reproductive dysfunction in captive-reared females. Reproductive dysfunction is closely linked to endocrine reproductive mechanisms. To better understand the reproductive dysfunction in captive broodstock, functional characterization of gonadotropins (GtHs: follicle stimulating hormone β subunit, fshβ; luteinizing hormone β subunit, lhβ; and glycoprotein α subunit, gpα) and sex steroids (17β-estradiol, E2; testosterone, T; progesterone; P) was performed using qRT-PCR, ELISA, in vivo, and in-vitro assay. The pituitary GtHs and gonadal steroids levels were significantly higher in ripen fish of both sexes. However, changes in lhβ and E2 levels in females were not significant in the developing and ripen stages. Furthermore, GtHs and steroids levels were lower in females compared to males throughout the reproductive cycle. In vivo administration of gonadotropin releasing hormone analogue (GnRHa) significantly increased the expression of GtHs in both dose- and time-related manners. The lower and higher doses of GnRHa led to successful spawning in male and female SYC, respectively. Sex steroids in vitro significantly inhibited the expression of lhβ in female SYC. Overall, GtHs were shown to play a vital role in final gonadal maturation, while steroids promoted negative feedback in the regulation of pituitary GtHs. Lower levels of GtHs and steroids might be key components in the reproductive dysfunction of captive-reared female SYC.

Reproductive Performance of Female Rabbits Inseminated with Extenders Supplemented with GnRH Analogue Entrapped in Chitosan-Based Nanoparticles.

Rabbit is a reflexively ovulating species. Accordingly, in the practice of artificial insemination (AI) ovulation must be induced via exogenous GnRH (Gonadotropin-Releasing Hormone) administration, which may be performed intramuscularly, subcutaneously, or intravaginally. Unfortunately, the bioavailability of the GnRH analogue when added to the extender is lower due to the proteolytic activity in the seminal plasma and the poor permeability of the vaginal mucosa. The aim of the study was to refine the practice of AI practice in rabbits by replacing parenteral GnRH analogue administration (subcutaneous, intravenous, or intramuscular injection) with intravaginal application, while reducing its concentration in the diluent. Extenders containing the buserelin acetate in chitosan-dextran sulphate and chitosan-alginate nanoparticles were designed and 356 females were inseminated. Reproductive performance of females inseminated with the two experimental extenders, receiving 4 μg of buserelin acetate intravaginally per doe, was compared with that in the control group, the does of which were inseminated with the extender without the GnRH analogue and induced to ovulate with 1 μg of buserelin acetate administered intramuscularly. The entrapment efficiency of the chitosan-dextran sulphate complex was higher than that of chitosan-alginate. However, females inseminated with both systems showed similar reproductive performance. We conclude that both nanoencapsulation systems are an efficient way of intravaginal ovulation induction, allowing a reduction in the level of the GnRH analogue normally used in seminal doses from 15-25 μg to 4 μg.

73 Comparison of GnRH Administration day in the 7 &amp; 7 Synch Versus 8 &amp; 6 Synch Protocol for Fixed-Timed Artificial Insemination in Beef Heifers

Abstract The study was conducted to identify effects of a decreased interval of progesterone on the ovulatory follicle before fixed-timed artificial insemination (FTAI) by altering the day of a gonadotropin-releasing hormone agonist (GnRH;00µg gonadorelin; Cystorelin) administration. Evaluation of the 7 &amp; 7 Synch and altered estrous synchronization protocols was done using estrus expression (EE) and FTAI pregnancy rates (PR). Using frozen conventional Angus semen (Select Sires, Inc. Plain City, OH), Angus-cross heifers (n = 68) from the University of Arkansas beef cattle research unit near Fayetteville were stratified into two treatment groups by cyclicity status (CYC) and age. Cyclicity status was determined by using a reproductive tract score (RTS) taken one week prior to beginning synchronization. Scores ranged from 1-5, where RTS 1-3 were considered pre- or peripubertal while scores 4 and 5 were considered cycling. Heifers with a RTS of and 2 were culled prior to synchronization. Each treatment used a controlled internal drug releasing device (CIDR; Eazi-breed; 1.38g progesterone) inserted intravaginally on –14 d simultaneous to the administration of a prostaglandin F2α analogue (PGF; 500 µg cloprostenol sodium; Synchsure). In the first treatment (7 &amp; 7), GnRH was administered on –7 d. In the second treatment (8 &amp; 6), GnRH was administered on –6 d. Both treatments were then administered PGF simultaneous to CIDR removal on 0d, 72 ±h prior to FTAI and the administration of GnRH. Estrus expression was recorded at the time of FTAI using an Estrotect patch (Rockway Inc., Spring Valley, WI). Estrus expression was determined as a patch with 50% or more of the color rubbed off. On the contrary, a patch with less than 50% of the color rubbed off, was not. Pregnancy rates was determined via ultrasound on 58 d. Estrus expression and PR were analyzed by treatment using the GLIMMIX procedure on SAS 9.4 (SAS Institute Inc., Cary, NC) with CYC as a fixed effect for EE; CYC and EE as fixed effects for PR. Statistical differences were determined with α ≤ 0.05 and tendencies were observed between 0.06-0.1. There was an effect of CYC on EE (P = 0.001) and a tendency to affect PR (P = 0.088). There was no treatment effect on EE (P = 0.892) or PR (P = 0.708). In conclusion, the altered time of GnRH administration in the 7 &amp; 7 synch at 72 ± hours did not affect EE or PR; however, research will continue to investigate adjusting length of time from PGF injection to FTAI to evaluate the effects.

Signal transduction of the insulin secretion induced by the chalcone analogue, (E)-3-(phenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one, and its role in glucose and lipid metabolism

A chalcone analogue, (E)-3-(phenyl)-1-(3,4,5-trimethoxyphenyl)prop-2-en-1-one (DMU 101), was synthesized using classic base catalysis and Claisen-Schmidt condensation, and then screened for its antidiabetic properties. The compound's effects on glucose and lipid metabolism were assayed in rats that were treated acutely and for a short time to elucidate its mechanism of action, evaluating glucose tolerance and lactate dehydrogenase activity in response to chalcone analogue administration. The chalcone's in vitro and ex vivo effects on glycogen, glucose, lipid and lipolysis were also investigated, as well as the mechanism by which it induces 45Ca2+ influx-mediated insulin secretion. The analogue (10 mg/kg) diminished glycemia, without inducing acute cell damage, increased glycogen content in the skeletal muscle and reduced serum triacylglycerol and total cholesterol, but did not alter high-density lipoprotein or low-density lipoprotein. Chalcone (10 μM) stimulated glucose uptake in the soleus muscle and did not modulate in vitro or ex vivo lipolysis. This analogue also increased insulin secretion by triggering calcium influx and blocking ATP-sensitive K+ channels and voltage-dependent calcium channels. However, it also modulated stored calcium via sarco/endoplasmic reticulum calcium ATPase (SERCA) and ryanodine receptor (RYR) activity. These findings indicate that this chalcone may induce cellular repolarization via a mechanism mediated by calcium-dependent potassium channels.