Hormone Activity Research Articles

Functional enrichment analysis of mutated genes in children with hyperthyroidism.

Hyperthyroidism in Chinese children is relatively high and has been increasing in recent years, which has a significant impact on their healthy development. Hyperthyroidism is a polygenic disorder that presents greater challenges in terms of prediction and treatment than monogenic diseases. This study aims to elucidate the associated functions and gene sets of mutated genes in children with hyperthyroidism in terms of the gene ontology through GO enrichment analysis and in terms of biological signaling pathways through KEGG enrichment analysis, thereby enhancing our understanding of the expected effects of multiple mutated genes on hyperthyroidism in children. Whole-exome sequencing was performed on the DNA samples of children with hyperthyroidism. Screening for pathogenic genes related to hyperthyroidism in affected children was performed using the publicly available disease databases Malacards, MutationView, and Clinvar, and the functions and influences of the identified pathogenic genes were analyzed using statistical analysis and the gene enrichment approach. Through GO enrichment analysis, it was found that the most significant gene ontology enrichment was the function "hormone activity" in terms of gene ontology molecular function. The corresponding mutated genes set that has common effects on hyperthyroidism in children included TG, CALCA, POMC, CGA, PTH, GHRL, FBN1, TRH, PRL, LEP, ADIPOQ, INS, GH1. The second most significant gene ontology enrichment was the function "response to peptide hormone" in terms of biological process. The corresponding mutated genes set that has common effects on hyperthyroidism in children included LRP6, TSC2, KANK1, COL1A1, CDKN1B, POMC, STAT1, MEN1, APC, GHRL, TSHR, GJB2, FBN1, GPT, LEP, ADIPOQ, INS, GH1. Through KEGG enrichment analysis, it was found that the most significant biological signaling pathway enrichment was the pathway "Thyroid hormone signaling pathway" function. The corresponding mutated genes set that has common effects on hyperthyroidism in children included NOTCH3, MYH7, TSC2, STAT1, MED13L, MAP2K2, SLCO1C1, SLC16A2, and THRB. The second most significant biological signaling pathway enrichment was the pathway "Hypertrophic cardiomyopathy" in terms of biological process. The corresponding mutated genes set that has common effects on hyperthyroidism in children included IGF1, CACNA1S, MYH7, IL6, TTN, CACNB2, LAMA2, and DMD. The mutated genes in children with hyperthyroidism were closely linked to function involved in "hormone activity" and "response to peptide hormone" in terms of the biological signaling pathway, and to the functional pathways involved in "Thyroid hormone signaling pathway" and "Hypertrophic cardiomyopathy" in terms of the biological signaling pathway.

Migration Studies and Endocrine Disrupting Activities: Chemical Safety of Cosmetic Plastic Packaging.

The endocrine activity and endocrine disruptor (ED) chemical profiles of eleven plastic packaging materials covering five major polymer types (3PET, 1HDPE, 4LDPE, 2 PP, and 1SAN) were investigated using in vitro cell-based reporter-gene assays and a non-targeted chemical analysis using gas chromatography coupled to mass spectrometry (GC-MS). To mimic cosmetic contact, six simulants (acidic, alkaline, neutral water, ethanol 30%, glycerin, and paraffin) were used in migration assays performed by filling the packaging with simulant. After 1 month at 50 °C, simulants were concentrated by Solid Phase Extraction (SPE) or Liquid-Liquid Extraction (LLE). The migration profiles of seven major endocrine disrupting chemicals detected from GC-MS in the different materials and simulants were compared with Estrogen Receptor (ER) and Androgen Receptor (AR) activities. With low extraction of ED chemicals in aqueous simulants, no endocrine activities were recorded in the leachates. Paraffin was shown to be the most extracting simulant of antiandrogenic chemicals, while glycerin has estrogenic activities. Overall, ED chemical migration in paraffin was correlated with hormonal activity. The NIAS 2,4-di-tert-butyl phenol and 7,9-di-tert-butyl1-oxaspiro (4,5) deca-6,9-diene-2,8-dione were two major ED chemicals present in all polymers (principally in PP and PE) and in the highest quantity in paraffin simulant. The use of glycerin and liquid paraffin as cosmetic product simulants was demonstrated to be relevant and complementary for the safety assessment of released compounds with endocrine activities in this integrated strategy combining bioassays and analytical chemistry approaches.

THU641 Single-cell Transcriptomic Analysis Reveal Dysregulated Immune Modulation In The Pituitaries Of Letrozole-induced Mouse Model Of PCOS

Abstract Disclosure: G. De Robles: None. The most common endocrine disorder, affecting both the reproduction and metabolism of females, is polycystic ovary syndrome (PCOS). Characterizations of the heterogeneous disorder include anovulation, biochemical hyperandrogenemia, insulin resistance, and obesity, which can be recapitulated with a letrozole-induced PCOS mouse model. Immune abnormalities have also been reported in PCOS human patients, including pro-inflammatory factor secretion imbalance and endothelial cell dysfunction. The extent to which the letrozole-induced mouse model for PCOS can represent these immune dysregulations remain unclear, specifically its relevance to disrupting hormone-regulating centers, such as the pituitary gland. Using a PCOS mouse model developed via letrozole induction, we performed single-cell mRNA sequencing on the pituitaries to study impairment in hormone activity and immune regulation. We also carried out a multiplexed immunoassay on stimulated splenocytes to profile cytokines under different immune cell activations. We identified B cells, neutrophils, microglia, T memory cells, and interestingly, sub-populations of macrophages in the pituitary. Differential expression analysis revealed affected genes in the total macrophages of PCOS mice, such as the up-regulation of Pf4, Il1a, and Ccl7. Differentially expressed genes, such as Lyz2, Ctss, Apoe, and H2-Aa, were also down-regulated in the T memory cells of PCOS mice. Pituitary cell types also exhibited dysregulated expressions, including lactotropes, corticotropes, gonadotropes, and somatotropes. Differences in cytokine expression from the multiplex immunoassays also allowed the mice to be distinct from those treated with letrozole or not via principal component analysis. Altogether, the letrozole-treated mice presented disrupted immune responses and hormonal imbalances in their transcription and cytokine profiles that further strengthens their ability to model PCOS. Presentation: Thursday, June 15, 2023

SAT367 A Rare Case of Ovarian Cellular Fibroma Producing Testosterone

Abstract Disclosure: H.K. Rai: None. P. Dandona: None. Background: Ovarian fibromas are hormonally inactive, benign sex cord-stromal tumors. However, the occurrence of ovarian fibromas in a woman presenting with post-menopausal bleeding, hirsutism, and elevated testosterone levels raises suspicion of such tumors being functionally active.Case: 62-year-old menopausal woman presented for evaluation of worsening facial hair for the past year. She reported vaginal spotting for the past two months and was following up with a gynecologist. She denied acne, male pattern baldness, or any other virilizing features. She was also recently diagnosed with polycythemia; hematological workup was remarkable for elevated testosterone. Her blood work was significant for elevated testosterone levels and hemoglobin, results as follows: total testosterone: 160ng/dl (2-45 ng/dL), free testosterone: 25.4pg/ml (0.1-6.4 pg/ml), sex hormone binding globulin (SHBG): 26 nmol/L (14-73 nmol/L), estradiol: <15 pg/ml (post-menopausal range: </=31 pg/ml), FSH: 17.3mIU/ml (23.0-116.3mIU/ml), LH: 19.1mIU/L (10.0-54.7 mIU/mL), prolactin: 5.7 ng/mL (2.0-20.0 ng/mL), DHEAS: 78 mcg/dL (12-133 mcg/dL), 8 AM cortisol: 17 mcg/dL (10-20 mcg/dL), ACTH: 11pg/ml (6-50pg/ml), Hb: 16.6g/dl (11.7-15.5 g/dL) and hematocrit: 49.8% (35.0-45.0%). Ultrasound pelvis showed heterogeneous thickened endometrium, small left-sided intramural leiomyoma of the uterus and ovaries were not well identified. MRI pelvis with and without contrast showed a 2.4 cm left uterine fibroid. A simple cyst was noted in the right ovary and two para-ovarian cysts were noted on the left ovary. The overall appearance of both ovaries was similar to a CT scan done a year earlier. She underwent a total hysterectomy with bilateral salpingo-oophorectomy. Surgical pathology was remarkable for cellular fibroma of both ovaries. After surgery, the patient's facial hair significantly improved, and she was noted to have normal testosterone levels (total testosterone: 23, free testosterone: 2.6, SHBG: 50). Her hemoglobin normalized as well, reaching a value of 13 g/dL. Conclusion: Our patient presented with post-menopausal bleeding, hirsutism, polycythemia, and increased testosterone levels. After she underwent total hysterectomy with bilateral salpingo-oopherectomy, her symptoms resolved. Testosterone and hemoglobulin levels returned to normal. Surprisingly, ovarian cellular fibroma on both sides was identified by surgical pathology. Ovarian cellular fibromas are rarely linked to endocrine activity, but with this case, we want to emphasize that its hormonal activity needs further exploration in the future. Presentation Date: Saturday, June 17, 2023

FRI367 An Unusual Presentation Of A Thyroid Nodule: A Thyroid Paraganglioma

Abstract Disclosure: M. Owrangi: None. F. Hasan: None. Introduction: Thyroid paraganglioma (PGL) is a rare thyroid tumor that originates from inferior laryngeal paraganglia. We present a case of a patient initially believed to have a thyroid nodule which turned out to be a PGL. Case Presentation: A 49 year-old white female with history of GERD and mild dysphagia who was found to have a left parathyroid adenoma vs. a left exophytic thyroid nodule. Previous ultrasounds had all showed slow but progressive enlargement of the lesion. Her labs had showed iPTH, Ca, TSH, and free T4 all within reference range and she was clinically euthyroid. She had 2 fine needle aspirations (FNA) which were both non diagnostic. She ultimately underwent surgical excision of the mass. The pathological examination showed cells that were positive for synaptophysin, chromogranin, GATA-3, S100, and neuron-specific enolase. They were negative for Ki-67, PTH, thyroglobulin, TTF-1, CK AE1/AE3, and CD 138. The overall findings were consistent with thyroid PGL. Discussion: In this case Thyroid PGL was diagnosed after pathological examination, including immunohistochemistry, was performed on a surgically excised sample, after 2 FNAs were non-diagnostic. Thyroid PGLs are elusive tumors. One study suggested that since they were first described in 1964, until 2015, there have only been 54 reported cases of thyroid PGLs, with a strong female predominance (88.9%). They often present as asymptomatic thyroid nodules and their diagnosis can be difficult by FNA alone as they can morphologically mimic medullary thyroid carcinoma, intrathyroidal parathyroid proliferation, metastatic neuroendocrine tumor, or calcitonin-negative neuroendocrine tumor of the thyroid gland (CNNETT). Thyroid PGLs are often benign, slow growing tumors and account for only 0.012% of all head and neck tumors with a malignancy rate of 4-16%. They usually present as single nodules averaging 3.5 cm and are often diagnosed with routine ultrasound assessment of the neck. Since they are associated with the parasympathetic nervous system, signs and symptoms including tachycardia, palpitations, and weight loss due to hormonal activity are classically absent from thyroid PGLs. In about 30% of cases, thyroid PGLs have a genetic predisposition and are more than one and associate with other tumors such as pheochromocytoma. Major hereditary disorders associated with paraganglioma include von Hippel-Lindau disease, multiple endocrine neoplasia, familial paraganglioma syndromes 1 to 4, and neurofibromatosis. Therefore, it is highly recommended that patients with a diagnosis of thyroid PGL undergo additional investigations with imaging, hormonal activity assessment, and genetic testing. Given the difference in management of thyroid PGLs compared to its cytology mimics, and their association with some familial cancer syndromes, use of immunohistochemical staining is crucial in making the correct diagnosis. Presentation: Friday, June 16, 2023

FRI370 Hyperthyroidism And Acromegaly In A Patient With A Mature Plurihormonal PIT1 Lineage PitNET/Adenoma

Abstract Disclosure: D. Slack: None. A.C. Levine: None. Background: TSH- and GH-secreting pituitary neuroendocrine tumors (PitNETs) are both rare entities, with an incidence of 1 per million people and 1-4 per million people, respectively. Thyrotroph, somatotroph, and lactotroph cells have the same progenitor, regulated by the PIT1 transcription factor. Thus, it is not unusual for PIT1 positive tumors to exhibit immunhistochemical expression of TSH, GH, and prolactin. It is vanishingly rare, however, for these tumors to secrete multiple biologically active hormones with apparent clinical sequelae. We herein report on a case of a patient with a plurihormonal PIT1 lineage PitNET secreting prolactin with secondary amenorrhea, TSH causing central hyperthyroidism and GH resulting in acromegaly. Clinical Case: A 42-year-old woman with a 1-year history of amenorrhea presented with 3 months of progressive weight loss, fatigue, palpitations, and tremulousness. She was found to have central hyperthyroidism, with an elevated free T4 (>7.77 ng/dL, nl 0.82 – 1.77) and inappropriately normal TSH (3.25 uIU/mL, nl 0.45 – 4.5). Full endocrine workup confirmed central hyperthyroidism with elevated free T4 (5.02 ng/dL) and TSH (4.68 uIU/mL) and also demonstrated hyperprolactinemia (122 ng/mL, nl 4.8 – 23.3 ng/mL), elevated IGF-1 (795 ng/mL, nl 91 – 308 ng/mL), GH (19 ng/mL, nl 0 – 10) and free alpha subunit (28 ng/mL, nl <1.02). Over the ensuing 4 months, she noted enlargement of her lips, nose, feet, and hands. MRI demonstrated a pituitary macroadenoma measuring 2.2 cm x 2.7 cm x 2 cm with asymmetric extension into the left cavernous sinus and mild elevation of the adjacent optic chiasm. She underwent an uncomplicated transsphenoidal resection of the tumor with no residual tumor noted on post-op MRI. Discharge medications were hydrocortisone 10 mg AM and, 5 mg early afternoon and levothyroxine 50 mcg daily. One month postoperatively, labs were notable for a low TSH (0.16 mIU/L), normal free T4 (1.62 ng/dL), down-trending IGF-1 (339 ng/mL), and normal prolactin (15.1 ng/mL). Additionally, AM cortisol and ACTH levels remained normal after holding her morning dose of hydrocortisone. She reported resolution of all presenting symptoms of thyrotoxicosis as well as decreasing size of her hands, feet, and nose. Pathology revealed a mature plurihormonal PIT1-lineage PitNET, with immunoreactivity for PIT1, GH, TSH, and prolactin and MIB-1 index of 3%. Conclusion: This case demonstrates the potential for PitNETs to secrete multiple biologically active pituitary hormones, including prolactin, TSH and GH, highlighting the importance of maintaining an index of suspicion for pituitary causes in the evaluation of thyrotoxicosis and of considering the plurihormonal potential of PitNETs in patients presenting with multiple endocrinopathies. Presentation: Friday, June 16, 2023

SAT505 Pericardial Effusion as The Primary Manifestation of Hypothyroidism

Abstract Disclosure: W. Lai: None. A. Karca: None. J. Zheng: None. Q. Shi: None. V.G. Kankani: None. A 50-year-old woman with no known past medical history, medications, or allergies. She presented with right arm pain, headache, neck swelling on the right side for 3 days. She concomitantly had loss of appetite, weight gain, drowsiness, and daytime somnolence. Denied any chest pain, nausea, or abdominal pain. Her vitals included a temperature of 96oF, blood pressure of 107/82mmHg, and respiratory rate of 8. She had hypoxia requiring 2L oxygen. On exam, heart sounds were distant. Significant tests included a TSH 69uIU/mL and FT4 <0.1ng/FL. Metabolic panel had a normal sodium 139mmol/L and glucose 116mg/dL. 3 a.m. cortisol level was 6.3ug/dL.EKG showed low-voltage QRS complexes. CTA chest revealed marked pericardial effusion. Echocardiogram showing septal motion abnormalities with large pericardial effusion (>20mm) suggestive of tamponade. Pericardiocentesis was performed and 800mL of serous fluid was drained. Fluid analysis showed total nucleated cell of 223/uL, lymphocyte 169.48 /uL, monocyte 51.29 /uL, RBC < 2000 /uL, protein 3.9g/dL, and glucose 81mg/dL. Pericardial effusion was negative for malignancy or infections. Patient was administered intravenous (IV) hydrocortisone, levothyroxine, and liothyronine. Her mentation and breathing gradually improved and she was discharged on oral medications. Large pericardial effusion due to hypothyroidism is rare ranging from 1-5%.[1,2] It is caused by increased permeability of pericardial capillaries with effusion of protein and glycosaminoglycan rich fluid.[3] Cardiac tamponade is an exceedingly rare presentation for hypothyroidism. Pericardial effusion secondary to hypothyroidism is treated with intravenous thyroxine. This case was complicated by concerns for myxedema crisis so glucocorticoid were given to treat possible adrenal insufficiency as the random cortisol was <18ug/dL. IV liothyronine was added to the therapy of this patient’s myxedema to provide biologic active thyroid hormone for faster onset though there is no consensus on optimal hormone treatment. [4] Pericardiocentesis is performed if tamponade is present such as this case.This case highlights variability in hypothyroidism presentation. Massive pericardial effusion complicated by cardiac tamponade in hypothyroidism is rare but exceedingly rare as primary symptom of presentation. 1. Sagrista-Sauleda J, Merce J, Permanyer-Maralda G, et al. Clinical clues to the causes of large pericardial effusions. Am J Med 2000; 109:95.2. Levy PY, Corey R, Berger P, et al. Etiologic diagnosis of 204 pericardial effusion. Medicine (Baltimore) 2003; 82:385.3. Badiu C MD, PhD. WILLIAMS TEXTBOOK OF ENDOCRINOLOGY. Acta Endocrinol (Buchar). 2019 Jul-Sep;15(3):416. doi: 10.4183/aeb.2019.416. PMCID: PMC6992389.4. Kwaku MP, Burman KD. Myxedema coma. J Intensive Care Med. 2007 Jul-Aug;22(4):224-31. doi: 10.1177/0885066607301361. PMID: 17712058. Presentation Date: Saturday, June 17, 2023

OR14-06 Serum Thyroid Hormones Increase At The Onset Of Lactation And Promote Metabolic Pathways Required For Human Milk Synthesis

Abstract Disclosure: H. Rostom: None. X. Meng: None. R. Humphrey: None. A. Fry: None. T. Elajnaf: None. F. Hannan: None. An increase in mammary metabolism is critical for initiating lactation during postpartum days 1-4. We utilised clinical and cellular approaches to investigate whether thyroid hormones, which promote lactation in rodents, are involved in initiating human lactation and regulating mammary metabolism. We recruited n=35 healthy pregnant women intending to breastfeed following informed consent and measured serum thyroid hormones (TSH and free T4) at 36 weeks’ gestation and on postpartum days 1-4 (1). Serum TSH significantly increased at post-partum day 1 compared with 36 weeks’ gestation (2.5±0.3 vs. 1.6±0.1 mU/L, p=0.001). This early postpartum rise in TSH was followed by a significant increase in free T4 on post-partum days 3 and 4 (11.7±0.2 vs. 10.5±0.2pmol/L at 36 weeks’ gestation, p<0.01). We hypothesised that thyroid hormones increase mammary metabolism to promote breast milk production. Reverse transcription-quantitative PCR (RT-qPCR) of genes encoding deiodinase enzymes (DIO1-3), which regulate intracellular thyroid hormone activity, was undertaken in lactating human mammary epithelial cells (HMECs) isolated from breast milk. This showed that DIO1, which converts T4 to T3, was expressed in lactating HMECs, whereas DIO2 and DIO3 were not detected. Moreover, RT-qPCR of the thyroid hormone receptor alpha and beta (THRA and THRB) genes in lactating HMECs showed that THRB has ∼4-fold greater expression than THRA (p<0.05, n=4). THRB phosphorylates Akt, which is required for initiating lactation. Consistent with this, cultured HMECs stimulated with 10nM T3, the most potent thyroid hormone, for 15min showed an ∼2-fold increase in Akt phosphorylation (p<0.0001, n=4). Akt regulates oxidative phosphorylation, which we assessed by measuring oxygen consumption rate (OCR) and ATP synthesis. HMECs treated with 10nM T3 for ≤8hrs showed a 2-fold increase in OCR (p<0.05, n=4) without any change in cellular ATP. These findings suggested that T3 uncoupled mitochondrial respiration from ATP synthesis. In support of this, RT-qPCR of cultured HMECs stimulated with 10nM T3 showed increased expression of genes encoding uncoupling proteins 2 and 3 (≥2-fold, p<0.01, n=4), which also function to divert substrates away from mitochondrial catabolism; and >20-fold increased expression of PPARGC1A (p<0.0001, n=4), which promotes mitochondrial biogenesis. In summary, these findings demonstrate that serum TSH and free T4 are increased at the onset of lactation. Moreover, our cellular studies indicate that thyroid hormones promote mammary mitochondrial biogenesis and may divert substrates used for ATP generation towards the synthesis of breast milk. Reference: (1) Rostom, H. et al. Protocol for an observational study investigating hormones triggering the onset of sustained lactation: the INSIGHT study. BMJ Open 12, e062478. Presentation: Friday, June 16, 2023

THU115 Sex-Specific And Shared Associations Between Vasopressin Levels And Body Composition In Adults With Obesity

Abstract Disclosure: F. Galbiati: None. M. Wronski: None. A. Aulinas Maso: None. M. Muhammed: None. R. Boutin: None. K. Liya: None. S. Carter: None. H. Nazarloo: None. J.M. Davis: None. K. Holman: None. J. Gydus: None. S. Smith: None. E. Asanza: None. M. Bredella: None. M. Torriani: None. F. Plessow: None. E.A. Lawson: Advisory Board Member; Self; OXT Therapeutics. Grant Recipient; Self; Tonix Pharmaceuticals. Background: Arginine-vasopressin (AVP) is a sexually dimorphic neurohormone shown in preclinical studies to have relevant metabolic effects, including reducing food intake, inducing lipolysis, and promoting muscle regeneration in male mice. However, findings are inconsistent, possibly due to the opposing effects of AVP at different receptor subtypes, and little is known about the effects of AVP on metabolism in humans. We hypothesized that AVP may act as signal of energy availability, such that in adults with obesity, integrated AVP levels around a standardized meal would be positively associated with BMI, adiposity, and lean mass. We also predicted that relationships between AVP and body composition measures would differ by sex. Methods: We performed a cross-sectional study of 53 adults with obesity (56% females; age [mean±SD] 33.7±6.2 years; BMI 36.9±4.9 kg/m2). We obtained plasma AVP levels fasting and 30, 60, and 120 minutes after a standardized meal. We computed area under the curve with respect to ground (AUC) for an integrated measure of AVP levels around the meal. Participants underwent body composition assessment by dual-energy X-ray absorptiometry (total fat, truncal fat, and lean mass) and magnetic resonance imaging (abdominal visceral and subcutaneous fat). We performed Pearson’s correlation (normally distributed variables) and Spearman’s correlation (non-normally distributed variables) to investigate the relationship between AVP levels and body composition parameters. Fisher’s Z test was performed to analyze the difference between correlation coefficients across sexes. Results: Age and AVP AUC did not differ based on sex (p=0.300). Total fat mass (p=0.013) was higher while total lean mass (p<0.0001) and abdominal visceral fat (p=0.001) were lower in females than males; BMI, truncal fat, and abdominal subcutaneous fat did not differ by sex (p’s≥0.09). Across all participants, AVP AUC levels were positively correlated with BMI (rs=0.36, p=0.008), total fat mass (r=0.33, p=0.013), truncal fat (r=0.35; p=0.010), abdominal subcutaneous fat (r=0.30, p=0.028), and total lean mass (r=0.38, p=0.005), but not with abdominal visceral fat (p=0.331). Within sex-based group, a robust positive correlation between AVP AUC and abdominal subcutaneous fat mass was present in males (r=0.56, p=0.004), but not females (r=0.04, p=0.592) [(by Fisher’s Z test, p=0.024). There were no other sex differences in correlations (by Fisher’s Z test, p≥0.108). Conclusions: Our data in humans showing a link between integrated AVP and body composition support preclinical data indicating that AVP is a metabolically active hormone. Additionally, we identified sex differences in the relationship between AVP and subcutaneous fat mass. Further investigation of sex-specific and shared metabolic effects of AVP in humans will be important. Presentation: Thursday, June 15, 2023

Terrestrial Compound Protein Replacing Dietary Fishmeal Improved Digestive Enzyme Activity, Immune Response, Intestinal Microflora Composition, and Protein Metabolism of Golden Pompano (Trachinotus ovatus).

Terrestrial compound protein (Cpro) can be potentially used to replace fishmeal (FM) in the marine carnivorous teleost, golden pompano (Trachinotus ovatus). Four isonitrogenous (45%) and isolipidic (12%) diets named FM30, AP80, PP80, and CP80 were formulated. FM30 (control) contained 30% FM and 25% basic protein, while AP80, PP80, and CP80 only contained 6% FM, where 80% FM and 25% basic protein of control diet were completely replaced by animal protein, plant protein, and Cpro, respectively. After golden pompano juveniles (initial weight: 10.32 ± 0.09 g) were, respectively, fed the four diets in floating sea cages for 10 weeks, the growth performance, intestinal digestive enzyme activity, and immune responses, protein metabolism indices of the CP80 group were similar to or better than those of the FM30 group (P > 0.05), and significantly better than those of the AP80 and PP80 groups. Specifically, the weight gain (WG), feed conversion ratio (FCR), activity of alanine transaminase (ALT), growth hormone (GH), and insulin-like growth factor-1 (IGF-1) contents of serum, mRNA level of interleukin-10 (il-10), zonula occludens-2 (zo-2), claudin-3, claudin-12, and eukaryotic translation initiation factor 4G (eif4g) were significantly higher, and the activity of α-amylase (AMS), lipase (LPS) in the foregut and midgut, interleukin-8 (il-8) expression in the intestine was significantly lower than that in the CP80 group, compared with those in AP80 and PP80 groups (P < 0.05). Moreover, the intestinal microflora composition of golden pompano fed with the CP80 diet was improved. Specifically, at the phylum level, the relative abundance of harmful bacterial strains cyanobacteria and TM7 of CP80 group was similar to those of FM30 group (P > 0.05), but was significantly lower than those of AP80 and PP80 groups (P < 0.05). At the genus level, the beneficial bacterial strains Agrobacterium and Blantia of CP80 group were also similar to those of FM30 group (P < 0.05), which were significantly higher than those of AP80 and PP80 groups, but the beneficial bacterial strains Bifidobacterium and Devosia of CP80 group were significantly higher than that in the other groups (P < 0.05). Besides, in diet CP80, the contents of amino acids and anti-nutritional factor, as well as the in vitro digestion rate were comparable to those of FM30, and the anti-nutritional factor content was between AP80 and PP80; total essential amino acids (EAAs) and methionine contents were higher than those in AP80, the glycine content was higher than that in PP80. Taken together, these results indicated that the CP80 diet had better amino acid composition and relatively low content of anti-nutritional factors, as well as high-digestion rate, and thus leads to the fish fed CP80 displaying improved effects in digestive enzyme activity, immune response, protein metabolism, and intestinal microbiota composition, which may be the important reasons to explain why that 80% of FM can be replaced by Cpro in the diet of golden pompano.

Peculiarities of treatment of patients with comorbid pathology: chronic pancreatitis and hypothyroidism, taking into account SEPP1 gene polymorphism (RS7579)

Optimization of therapeutic regimens during the treatment of the polymorbid course of chronic pancreatitis combined with hypothyroidism is an important task of modern science.&#x0D; Aim: to treat patients with comorbid pathology: chronic pancreatitis and hypothyroidism, taking into account the polymorphism of the SEPP1 gene (RS7579)&#x0D; Materials and methods. During the research, we examined 128 people. Patients were divided into 3 groups. The first group included 48 patients with chronic pancreatitis, the second - 50 patients with chronic pancreatitis in combination with hypothyroidism, and the third - 30 practically healthy people.&#x0D; Results. Symptoms of maldigestion decreased in 72 % of the examined patients. Signs of nutritional deficiency have significantly decreased, and general well-being has improved. Multicomponent therapy also affected mood, sleep, and reduced irritability and symptoms of depression and anxiety disorders. A multisystemic polysyndromic approach to treatment led to improvements in both pancreatic and thyroid function. The effectiveness of the treatment strategy for patients with chronic pancreatitis was dependent on individual characteristics, such as the severity of chronic pancreatitis, the presence of primary hypothyroidism, the degree of selenium deficiency and concomitant symptoms, taking into account polymorphic variants of the SEPP1 (rs7579) gene. Selenoid deficiency decreased, especially in the group with a combination of chronic pancreatitis and hypothyroidism. The improvement in thyroid hormone activity included a 40.46 % decrease in blood TSH and a 2.5-fold increase in free T4.&#x0D; Conclusions. The program of complex therapy led to the normalization of the condition of patients with the G-allele genotype of the SEPP1 gene (rs7579), as evidenced by significant improvements in most of the analyzed indicators. The concentration of fecal elastase 1 and blood selenoprotein P significantly increased, and the level of serum pancreatic α-amylase significantly decreased in carriers of the AA genotype. Under the influence of therapy, there were also changes in the hormonal activity of the thyroid gland, a decrease in the concentration of total metabolites of NO, and an improvement in the health indicators of the cardiovascular system. However, for patients with the AA genotype of the SEPP1 (rs7579) gene, continuation of therapy remains important to achieve an optimal condition, in particular, to manage cholesterol levels and other cardiovascular risk factors

Tridax procumbens leaf antioxidants and hormonal activity ameliorate variable stress-induced erectile and reproductive impairments in Wistar rats

Tridax procumbens leaf antioxidants and hormonal activity ameliorate variable stress-induced erectile and reproductive impairments in Wistar rats

Reproductive disorders linked to the interaction between sex steroid and thyroid hormonal activities, oxidative stress responses, and the rate of metabolism of tris (1,3-dichloro-2-propyl) phosphate (TDCPP) in zebrafish

The objective of this study was to assess the thyroid hormone disruption and reproductive dysfunction effects of the bioaccumulation and rate of mechanism in zebrafish exposed to tris(1,3-dichloro-2-propyl) phosphate (TDCPP), with stress responsiveness. The fish were exposed to test concentrations of TDCPP (0, 0.06, 0.3, 1.5 µg/mL) for 21 days, in accordance with no observed adverse effect level (i.e., < EC10) for zebrafish embryos. The bioaccumulation of TDCPP was found to be significantly higher in female zebrafish, while the metabolic rate was significantly higher in male zebrafish at all concentrations studied. The thyroid hormone (triiodothyronine [T3] and thyroxine [T4]) levels and sex steroid (i.e., estrogen, androgen, and progesterone) levels were significantly increased only in female zebrafish exposed to TDCPP, and no significant difference was observed in male zebrafish, although their cortisol levels increased. The response to TDCPP can, therefore, be considered sex-specific. The results of this study demonstrate for the first time, that the different response in the bioaccumulation and metabolic rate of TDCPP in males and females. The results also indicate that TDCPP alters thyroid hormone levels, furthermore, as steroidogenesis is related to reproductive function with differing response in males and females. TDCPP can be assumed to exert reproductive toxicity via disruption of thyroid and steroid synthesis through a slow metabolic rate in the whole body after exposure. Consequently, our proposed methodological approach to assess the interactions of thyroid and steroid biosynthesis and metabolic rate of TDCPP with reproductive toxicity will serve a testing strategy to examine the adverse outcomes of emerging environmental chemicals.

Cerebral blood flow and cerebrovascular reactivity are modified by maturational stage and exercise training status during youth.

What is the central question of this study? Gonadal hormones modulate cerebrovascular function while insulin-like growth factor 1 (IGF-1) facilitates exercise-mediated cerebral angiogenesis; puberty is a critical period of neurodevelopment alongside elevated gonadal hormone and IGF-1 activity: but whether exercise training across puberty enhances cerebrovascular function is unkown. What is the main finding and its importance? Cerebral blood flow is elevated in endurance trained adolescent males when compared to untrained counterparts. However, cerebrovascular reactivity to hypercapnia is faster in trained vs. untrained children, but not adolescents. Exercise-induced improvements in cerebrovascular function are attainable as early as the first decade of life. Global cerebral blood flow (gCBF) and cerebrovascular reactivity to hypercapnia ( ) are modulated by gonadal hormone activity, while insulin-like growth factor 1 facilitates exercise-mediated cerebral angiogenesis in adults. Whether critical periods of heightened hormonal and neural development during puberty represent an opportunity to further enhance gCBF and is currently unknown. Therefore, we used duplex ultrasound to assess gCBF and in n=128 adolescents characterised as endurance-exercise trained (males: n=30, females: n=36) or untrained (males: n=29, females: n=33). Participants were further categorised as pre- (males: n=35, females: n=33) or post- (males: n=24, females: n=36) peak height velocity (PHV) to determine pubertal or 'maturity' status. Three-factor ANOVA was used to identify main and interaction effects of maturity status, biological sex and training status on gCBF and . Data are reported as group means (SD). Pre-PHV youth demonstrated elevated gCBF and slower mean response times than post-PHV counterparts (both: P≤0.001). gCBF was only elevated in post-PHV trained males when compared to untrained counterparts (634(43) vs. 578(46)mlmin-1 ; P=0.007). However, mean response time was faster in pre- (72(20) vs. 95(29)s; P≤0.001), but not post-PHV (P=0.721) trained youth when compared to untrained counterparts. Cardiorespiratory fitness was associated with gCBF in post-PHV youth (r2 =0.19; P≤0.001) and mean response time in pre-PHV youth (r2 =0.13; P=0.014). Higher cardiorespiratory fitness during adolescence can elevate gCBF while exercise training during childhood primes the development of cerebrovascular function, highlighting the importance of exercise training during the early stages of life in shaping the cerebrovascular phenotype.

Evaluation of the Toxicity Potential of the Metabolites of Di-Isononyl Phthalate and of Their Interactions with Members of Family 1 of Sulfotransferases-A Computational Study.

Di-isononyl phthalates are chemicals that are widely used as plasticizers. Humans are extensively exposed to these compounds by dietary intake, through inhalation and skin absorption. Sulfotransferases (SULTs) are enzymes responsible for the detoxification and elimination of numerous endogenous and exogenous molecules from the body. Consequently, SULTs are involved in regulating the biological activity of various hormones and neurotransmitters. The present study considers a computational approach to predict the toxicological potential of the metabolites of di-isononyl phthalate. Furthermore, molecular docking was considered to evaluate the inhibitory potential of these metabolites against the members of family 1 of SULTs. The metabolites of di-isononyl phthalate reveal a potency to cause liver damage and to inhibit receptors activated by peroxisome proliferators. These metabolites are also usually able to inhibit the activity of the members of family 1 of SULTs, except for SULT1A3 and SULT1B1. The outcomes of this study are important for an enhanced understanding of the risk of human exposure to di-isononyl phthalates.

Balanophora genomes display massively convergent evolution with other extreme holoparasites and provide novel insights into parasite-host interactions.

Parasitic plants have evolved to be subtly or severely dependent on host plants to complete their life cycle. To provide new insights into the biology of parasitic plants in general, we assembled genomes for members of the sandalwood order Santalales, including a stem hemiparasite (Scurrula) and two highly modified root holoparasites (Balanophora) that possess chimaeric host-parasite tubers. Comprehensive genome comparisons reveal that hemiparasitic Scurrula has experienced a relatively minor degree of gene loss compared with autotrophic plants, consistent with its moderate degree of parasitism. Nonetheless, patterns of gene loss appear to be substantially divergent across distantly related lineages of hemiparasites. In contrast, Balanophora has experienced substantial gene loss for the same sets of genes as an independently evolved holoparasite lineage, the endoparasitic Sapria (Malpighiales), and the two holoparasite lineages experienced convergent contraction of large gene families through loss of paralogues. This unprecedented convergence supports the idea that despite their extreme and strikingly divergent life histories and morphology, the evolution of these and other holoparasitic lineages can be shaped by highly predictable modes of genome reduction. We observe substantial evidence of relaxed selection in retained genes for both hemi- and holoparasitic species. Transcriptome data also document unusual and novel interactions between Balanophora and host plants at the host-parasite tuber interface tissues, with evidence of mRNA exchange, substantial and active hormone exchange and immune responses in parasite and host.

Novel RNA-Seq Signatures Post-Methamphetamine and Oxycodone Use in a Model of HIV-Associated Neurocognitive Disorders.

In the 21st century, the effects of HIV-associated neurocognitive disorders (HAND) have been significantly reduced in individuals due to the development of antiretroviral therapies (ARTs). However, the growing epidemic of polysubstance use (PSU) has led to concern for the effects of PSU on HIV-seropositive individuals. To effectively treat individuals affected by HAND, it is critical to understand the biological mechanisms affected by PSU, including the identification of novel markers. To fill this important knowledge gap, we used an in vivo HIV-1 Transgenic (HIV-1 Tg) animal model to investigate the effects of the combined use of chronic methamphetamine (METH) and oxycodone (oxy). A RNA-Seq analysis on the striatum-a brain region that is primarily targeted by both HIV and drugs of abuse-identified key differentially expressed markers post-METH and oxy exposure. Furthermore, ClueGO analysis and Ingenuity Pathway Analysis (IPA) revealed crucial molecular and biological functions associated with ATP-activated adenosine receptors, neuropeptide hormone activity, and the oxytocin signaling pathway to be altered between the different treatment groups. The current study further reveals the harmful effects of chronic PSU and HIV infection that can subsequently impact neurological outcomes in polysubstance users with HAND.

Seasonal expressions of the translocator protein (18 kDa), voltage-dependent anion channel, and steroidogenic acute regulatory protein in the scent glands of muskrats (Ondatra zibethicus)

Steroidogenesis machinery involves the steroidogenic acute regulatory protein (StAR), which regulates cholesterol transfer within the mitochondria, and the transport of cholesterol via a channel composed of 18-kDa translocator protein (TSPO), the voltage-dependent anion channel (VDAC) plus some accessory proteins. In this study, we investigated the immunolocalizations and expressions of StAR, TSPO, VDAC and cytochrome P450 side chain cleavage enzyme (P450scc, CYP11A1) in the scent glands of muskrats (Ondatra zibethicus) during the breeding and non-breeding periods. StAR, TSPO, VDAC and CYP11A1 were immunolocalized in the scent glandular, interstitial and epithelial cells in both breeding and non-breeding seasons with stronger immunostaining in the breeding season. The mRNA expression levels of StAR, TSPO, VDAC and CYP11A1 were higher in the scent glands of the breeding season than those of the non-breeding season. The circulating follicle stimulating hormone (FSH), luteinizing hormone (LH) and testosterone (T) as well as scent glandular T and dihydrotestosterone (DHT) concentrations were also significantly higher in the breeding season. Additionally, the transcriptomic study in the scent glands identified that differentially expressed genes might be related to the lipid metabolic process, integral component of membrane, and steroid hormone receptor activity and hormone activity using GO analysis. Further in vitro study verified that StAR, TSPO, VDAC and CYP11A1 expression levels increased significantly after human chorionic gonadotropin, hCG/FSH treatment compared with the control group. The KEGG pathway enriched by differentially expressed genes detected to be involved in endocrine system or amino acid metabolism. These findings suggested that the scent glands of the muskrats have ability to synthesize steroids de novo, and that the steroid hormones may have an important regulatory role in the scent glandular function via an autocrine/paracrine pathway.

Endocrine disruptors in Adansonia digitata (Linn) extract induce alteration of female Wistar rats’ oestrous cycle, hormone and lipid profiles

ObjectiveHexane-acetyl acetate (HAAF) and acetyl acetate–methanol fractions (AAMF) but not aqueous methanol (AQMF) and aqueous fractions (AQF) of Adansonia digitata Linn root bark induce reproductive effects in female Wistar rats. The current study investigated the exclusive components of HAAF, AAMF, AQMF, and AQF of Adansonia digitata Linn root bark and the effect of AAMF on the female Wistar rat's oestrous cycle progression, and hormone and lipid profiles. MethodologyGas chromatography and mass spectrometry explored the components of HAAF, AAMF, AQMF, and AQF. Mature female Wistar rats with a proven 4–5-days oestrous cycle were synchronised and randomly assigned into three treatment groups of 30 rats each on the day of proestrus. For seven days, rats in the different groups received 0, 150, and 300 mg kg-1 body weights of AAMF, respectively. Six rats were euthanised from each group based on a standard oestrous stage-timed sequence. The oestrous stage, hormone profile (oestrogen, progesterone, progesterone/oestrogen ratio, and FSH) and lipid profile (Total cholesterol-TC, Triglycerols, High-HD and low density-LD lipid cholesterol) of the euthanised rats were determined. Resultstricosene, cyclopentadecanone 2-hydroxy-, oleic acid, and 9,17-octadecadienal, were exclusively found in HAAF and AAMF. The oestrous stage, serum hormone and lipids varied significantly (p < 0.05) between treatment groups. AAMF fraction induced sustained progesterone levels and depleted oestrogen levels, and TC and LDL were inversely related to serum oestrogen levels. DiscussionThe results suggest a depression of oestrogen and sustenance of progesterone-mediated effects, respectively, on GnRH surge. Oleic acid in AAMF may be responsible for its reproductive effects. ConclusionAAMF fraction of A. digitata (L) root bark disrupts the endocrine activity in female Wistar rats. The oleic acid component of the AAMF fraction may be responsible for modulating the activities of reproductive hormones. The authors recommend further studies to ascertain the significance of Adansonia digitata extract's oleic acid in regulating the female reproductive cycle.

The protective effect of hydroalcoholic extract of Ephedra pachyclada leaves on ovarian damage induced by cyclophosphamide in rat: An experimental study.

Cyclophosphamide (CP) is an anticancer drug that acts as an alkylation agent after metabolism in the liver. CP has toxic effects on the body's cells, especially the reproductive system's function, and causes infertility. Moreover, medicinal plants have few side effects and are psychologically acceptable to patients. This study aimed to investigate the impact of Ephedra pachyclada hydroalcoholic extract (EPHE) on ovarian tissue and hypothalamic-pituitary-gonadal axis in rats treated with CP. In this experimental study, 48 adult female Wistar rats (180-200 gr, 9-10 wk) were randomly assigned to 6 experimental groups (n = 8/each): (a) control; (b) sham; (c) CP; (d) CP+250 mg/kg EPHE; (e) CP+500 mg/kg EPHE; (f) CP+1000 mg/kg EPHE. On the 29 day of the experiment, serum was collected; serum concentration of the luteinizing hormone, follicle-stimulating hormone, estrogen, progesterone, and antioxidant activity were measured. The number of ovarian follicles were also counted. In the CP groups, serum concentrations of follicle-stimulating hormone and luteinizing hormone significantly increased, and estrogen and progesterone significantly decreased (p 0.05). EPHE significantly compensated for the complications caused by CP and 1000 mg/kg had the greatest effect. Antioxidant reduction by CP was significantly enhanced by EPHE, especially at higher doses (p 0.05). The number of primordial, primary, secondary, and Graafian follicles showed a significant decrease in CP groups and EPHE groups showed a significant increase compared to the CP. EPHE showed that the concentration of 1000 mg/kg was more effective than other doses (p 0.05). In addition to proving the effect of EPHE on the hypothalamic-pituitary-gonadal axis, our investigation showed antioxidant properties, which can be an effective factor in CP-treated rats.