Hormone Secretion Research Articles

PRECOCIOUS PUBERTY: EPIDEMIOLOGY, CLINICAL PRESENTATION, DIAGNOSIS, AND ETIOLOGIES

Precocious puberty, defined as the onset of sexual characteristics before the age of 8 in girls and 9 in boys, can arise from various causes, including central and peripheral mechanisms. While central precocious puberty (CPP) originates from premature activation of the hypothalamic-pituitary axis, peripheral precocious puberty (PPP) results from gonadal or adrenal hormone secretion independent of hypothalamic control. We conducted a retrospective study spanning eight years, from 2015 to 2023, at the Mohamed 6 University Hospital in Marrakech, Morocco, to investigate the epidemiological, clinical findings, laboratory, and etiological aspects of precociuos puberty in 12 children. We found a predominance of CPP, particularly in girls, with breast development being the most common clinical sign. In boys, early puberty typically presented with pubic hair development and increased penile size. Diagnostic evaluation included hormonal assays and imaging studies, with elevated levels of gonadal hormones confirming the diagnosis. CPP was predominantly idiopathic in girls, while traumatic brain injury and CNS lesions were common causes in boys. Adrenal disorders, including congenital adrenal hyperplasia, accounted for PPP cases. Brain imaging was crucial for identifying central lesions, while adrenal imaging aided in diagnosing adrenal pathologies. Despite limitations such as retrospective design and incomplete data, our study emphasizes the importance of early recognition and appropriate diagnostic procedures for children showing signs of early puberty to optimize management and outcomes.

Secondary hyperparathyroidism: Update

Secondary hyperparathyroidism is a clinical condition characterized by an increase in the synthesis and secretion of parathyroid hormone (PTH). Its presentation will be conditioned by the development of stimuli such as hyperphosphatemia, hypocalcemia, vitamin D deficiency, and PTH resistance. The most common cause of secondary hyperparathyroidism is chronic kidney disease, a pathological condition in which all the afore mentioned stimuli converge. Secondary hyperparathyroidism is evidenced by an increase in the size of the parathyroid glands, favored by cellular hyperplasia and hypertrophy. At the bone level, there will be an increase in the quantity and activity of osteoblasts and osteoclasts, leading to bone with unusual structural characteristics. Symptoms related to the disease include itching, bone pain, concentration alteration, and depression. In the long term, patients have a higher risk of cardiovascular mortality. Therapeutic options include calcimimetics, phosphate binders, vitamin D supplements, and surgery.

Zinc deficiency deteriorates ovarian follicle development and function by inhibiting mitochondrial function

Zinc (Zn) is a crucial trace element essential for human growth and development, particularly for reproductive health. Previous research has shown a decrease in serum zinc concentration with age and individuals with conditions such as polycystic ovary syndrome (PCOS) and diabetes mellitus. However, the specific effects of zinc deficiency on the female reproductive system, especially ovarian function, are not fully understood. In our study, we observed a significant reduction in the total number of follicles and mature follicles in the zinc deficiency group. This reduction correlated with decreased level of anti-Mullerian hormone (AMH) and abnormal gene expression affecting hormone secretion regulation. Furthermore, we found that zinc deficiency disrupted mitochondrial dynamics, leading to oxidative stress in the ovaries, which further inhibited autophagy and increased ovarian apoptosis. These changes ultimately resulted in the failure of germinal vesicle breakdown (GVBD) and reduced oocyte quality. Meanwhile, administration of zinc glycine effectively alleviated the oocyte meiotic arrest caused by dietary zinc deficiency. In conclusion, our findings demonstrated that dietary zinc deficiency can affect hormone secretion and follicle maturation by impairing mitochondrial function and autophagy.

Influenza A virus infection disrupts the function of syncytiotrophoblast cells and contributes to adverse pregnancy outcomes.

Pregnancy heightens susceptibility to influenza A virus (IAV) infection, thereby increasing the risk of severe pneumonia and maternal mortality. It also raises the chances of adverse outcomes in offspring, such as fetal growth restriction, preterm birth, miscarriage, and stillbirth in offsprings. However, the underlying mechanisms behind these effects remain largely unknown. Syncytiotrophoblast cells, crucial in forming the placental barrier, nutrient exchange and hormone secretion, have not been extensively studied for their responses to IAV. In our experiment, we used Forskolin-treated BeWo cells to mimic syncytiotrophoblast cells in vitro, and infected them with H1N1, H5N1 and H7N9 virus stains. Our results showed that syncytiotrophoblast cells, with their higher intensity of sialic acid receptors, strongly support IAV infection and replication. Notably, high-dose viral infection and prolonged exposure resulted in a significant decrease in fusion index, as well as gene and protein expression levels associated with trophoblast differentiation, β-human chorionic gonadotropin secretion, estrogen and progesterone biosynthesis, and nutrient transport. In pregnant BALB/c mice infected with the H1N1 virus, we observed significant decreases in trophoblast differentiation and hormone secretion gene expression levels. IAV infection also resulted in preterm labor, fetal growth restriction, and increased maternal and fetal morbidity and mortality. Our findings indicate that IAV infection in syncytiotrophoblastic cells can result in adverse pregnancy outcomes by altering trophoblast differentiation, suppressing of β-hCG secretion, and disrupting placental barrier function.

N-ethylhexedrone: a very long and bad trip! A Case series.

N-ethylhexedrone (NEH) is a new cathinone derivative with, currently, low toxicocokinetic, and toxicocodynamic knowledge. We present 3 documented clinical cases of NEH intoxication with plasma, and urine concentrations. A thorough search for metabolites was performed. The 3 patients were admitted to the emergency department, and 2 out of the 3 were hospitalized for an extended period. While recovering from the drug effects, 12 to 24 hours after nasal intake of New Psychoactive Substance (NPS), the patients described the following disorders: anxiety, feelings of persecution, asthenia, anhedonia, abulia, psychomotor slowing, and loss of consciousness. NEH was identified in all samples by liquid chromatography-high resolution mass spectrometry (LC-HRMS), and quantified by liquid chromatography coupled to tandem mass spectrometry (LC-MS-MS). Quantitative analysis showed decreasing concentrations over time: for case 1, from 97.2 (Day 1, D1) to 0.7 (Day 7, D7) µg/L for plasma, and from 724 (D1) to 0.5 (D7) µg/L for urine. NEH concentration of 7.9 µg/L was found in the plasma collected at admission for case 2. For case 3: concentrations ranging from 49 (D1) to 1.8 (D7) µg/L in plasma, and from 327.3 (Day 5, D5) to 116.8 (D7) µg/L in urine were found. NEH was no longer detected in the urine sample at Day 10. Elimination half-life was estimated at 19, and 28 hours in patients 1 and 3, respectively. Four metabolites were identified in blood and urine: reduced NEH, dealkyl-NEH, reduced dealkyl-NEH, and hydroxy-NEH. The cases presented highlight the long detectable lifetime of NEH. Characterization of the metabolites will allow better identification of the consumption of this drug. Serious adverse events can be observed after NEH consumption, as 2 out of 3 patients required intubation and ventilation. A syndrome of inappropriate antidiuretic hormone secretion (SIADH) was also diagnosed. Two out of the three cases are notable because of the number of samples collected and because NEH was the only drug of abuse detected.

Investigating GABA neuron-specific androgen receptor knockout in two hyperandrogenic models of PCOS.

Androgen excess is a hallmark feature of polycystic ovary syndrome (PCOS), the most common form of anovulatory infertility. Clinical and preclinical evidence links developmental or chronic exposure to hyperandrogenism with programming and evoking the reproductive and metabolic traits of PCOS. While critical androgen targets remain to be determined, central GABAergic neurons are postulated to be involved. Here, we tested the hypothesis that androgen signalling in GABAergic neurons is critical in PCOS pathogenesis in two well-characterised hyperandrogenic mouse models of PCOS. Using cre-lox transgenics, GABA-specific androgen receptor knockout (GABARKO) mice were generated and exposed to either acute prenatal androgen excess (PNA) or chronic periperpubertal androgen excess (PPA). Females were phenotyped for reproductive and metabolic features associated with each model and brains of PNA mice were assessed for elevated GABAergic input to GnRH neurons. Reproductive and metabolic dysfunction induced by PPA, including acyclicity, absence of corpora lutea, obesity, adipocyte hypertrophy and impaired glucose homeostasis, was not different between GABARKO and WT mice. In PNA mice, acyclicity remained in GABARKO mice while ovarian morphology and luteinising hormone secretion was not significantly impacted by PNA or genotype. However, PNA predictably increased the density of putative GABAergic synapses to GnRH neurons in adult WT mice, and this PNA-induced plasticity was absent in GABARKO mice. Together, these findings suggest that while direct androgen signalling in GABA neurons is largely not required for the development of PCOS-like traits in androgenised models of PCOS, developmental programming of GnRH neuron innervation is dependent upon androgen signalling in GABA neurons.

Cabergoline Targets Multiple Pathways to Inhibit PRL Secretion and Increases Stromal Fibrosis.

Unravel potential mechanism(s) of the on- and off-target actions of dopamine agonist therapy in both human prolactinoma tumor and neighboring stromal and immune cells. Five surgically resected prolactinomas from 3 cabergoline (CBG)-treated and 2 treatment naive patients were analyzed by single cell RNA sequencing (scRNA-seq) to compare the cellular composition and transcriptional landscape. Six major cell populations that included tumor (88.2%), immune (5.6%), stromal (4.9%), progenitor cells (0.6%), proliferating cells (0.4%), and erythrocytes (0.2%) were observed. Tumor cells from CBG-treated patients expressed lower levels of genes that regulated hormone secretion, such as SCG2, VGF, TIMP1, NNAT, and CALD1, consistent with the inhibitory effects of CBG on hormone processing and secretion. Interestingly, we also observed an increased number of CD8+ T cells in the CBG-treated tissues. These cytotoxic CD8+ T cells expressed killing granule components, such as perforin and the granzymes GZMB, GNLY and KLRD1 as well as the inflammatory cytokine CCL5. Immune cell activation of these CD8+ T cells was further analyzed in a compartment-specific manner, and increased CD25 (IL2R) expression was noted in the CD8+ T cells from CBG-treated samples. Additionally, and confirming prior reports, we noted a higher stromal cell population in CBG-treated samples. Our scRNAseq studies revealed key differences in the transcriptomic features of CBG-treated and untreated PRLomas in both tumor and microenvironment cellular constituents, and for the first time describe previously unknown activation of CD8+ T cells following CBG-treatment which may play a role in the tumoricidal actions of CBG.

Interference with VIP to distinguish between real and false VIPoma:national study from the French Endocrine Tumors Group

Abstract Background Vasoactive Intestinal Peptide-secreting tumors (VIPomas) are digestive neuroendocrine tumors in which the hormonal secretion is life threatening. Biological confirmation is obtained by demonstrating an elevation in plasma VIP, usually using radioimmunoassay (RIA) method. In some cases, an analytical interference is suspected. We developed three different techniques to detect the interference in VIP RIA. Methods Three techniques were used: RIA after Sephadex column chromatography separation, RIA after Polyethylene Glycol (PEG) precipitation and125I-labelled VIP binding test. We included patients with suspicion of false positive VIP (FPV) elevation. We then compared results with those of a group of ‘real’, proven VIPoma (RV). Results A total of 15 patients with FPV elevation and 9 RV patients were included. Interference was detected in all FPV patients versus none in RV. Clinical and biochemical parameters did not differ between FPV and RV patients, but VIP concentration in RIA was significantly higher in FVP patients than in RV patients (228pmol/l vs 66 pmol/l, p=0.038). Using 125I-labelled VIP binding test, median proportion of radioactivity in the pellet was significantly higher in FVP than in RV patients (53% vs 13%, p < 0.0001). A 20.5% threshold presented excellent performances (Sensitivity 100% [79.6-100], specificity 100% [70.1-100]). Conclusions We developed three different laboratory techniques to reveal interference in RIA VIP assays. The diagnostic performance of all three was excellent. These techniques must be employed in cases of discordance between VIP elevation and clinical presentation.

Potential Metabolic Pathways Involved in Osteoporosis and Evaluation of Fracture Risk in Individuals with Diabetes

Diabetes has a significant global prevalence. Chronic hyperglycemia affects multiple organs and tissues, including bones. A large number of diabetic patients develop osteoporosis; however, the precise relationship between diabetes and osteoporosis remains incompletely elucidated. The activation of the AGE-RAGE signaling pathway hinders the differentiation of osteoblasts and weakens the process of bone formation due to the presence of advanced glycation end products. High glucose environment can induce ferroptosis of osteoblasts and then develop osteoporosis. Hyperglycemia also suppresses the secretion of sex hormones, and the reduction of testosterone is difficult to effectively maintain bone mineral density. As diabetes therapy, thiazolidinediones control blood glucose by activating PPAR-γ. Activated PPAR-γ can promote osteoclast differentiation and regulate osteoblast function, triggering osteoporosis. The effects of metformin and insulin on bone are currently controversial. Currently, there are no appropriate tools available for assessing the risk of fractures in diabetic patients, despite the fact that the occurrence of osteoporotic fractures is considerably greater in diabetic individuals compared to those without diabetes. Further improving the inclusion criteria of FRAX risk factors and clarifying the early occurrence of osteoporosis sites unique to diabetic patients may be an effective way to diagnose and treat diabetic osteoporosis and reduce the risk of fracture occurrence.

G-Protein and G-Protein Coupled Receptors: Implications in Regulation of Immune Response

The guanine nucleotide binding proteins (G proteins) act as molecular switches of ‘on’ and ‘off’ when bound to GTP and GDP respectively while the guanine protein coupled receptors (GPCRs) are membrane bound receptors whereby extracellular substances (ligands)communicate signals from these substances to an intracellular molecule the G-proteins which in turn bind and activate or inhibit downstream effect or molecules causing cellular responses. This review is aimed at exploring the concept and mechanism of G-proteins and GPCR and their implication in immune response. The GPCR can be activated by various physiological or pathological processes cellular metabolism, hormones, neuro-transmitters, chemokines, autocrines, paracrines, endocrine and exocrine secretions which play an important role in relaying or routing signals to several intracellular pathways. The signal transduction by the extracellular activation or inhibition of the GPCR mediate metabolic enzymes, ion channels, transporters, cellular gene transcription, migration, survival, activation, differentiation and cytokine secretion of immune cells resulting in the synthesis and regulation of embryonic development, gonadal development, learning /memory organismal homeostasis, hematopoiesis and immune dynamics. Therefore, G proteins and GPCRs signaling systems are key determinants in innate and adaptive immunity. The signal transduction of G-Protein and GPCR by cytokine chemotaxis as Chronic inflammatory mediators is associated with tumorigenesis, metastasis with potential antagonism for appropriate targeted therapy.

Revolutionizing Infertility Management through Novel Peptide-based Targets.

Around 48 million couples and 186 million people worldwide have infertility; of these, approximately 85% have an identifiable cause, the most common being ovulatory dysfunctions, male infertility, polycystic ovary syndrome, and tubule disease. The remaining 15% have infertility for unknown reasons, including lifestyle and environmental factors. The regulation of the hypothalamic- pituitary-adrenal axis (HPA) is crucial for the secretion of gonadotropin-releasing hormone (GnRH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH), which are essential for female reproductive functions. GnRH is the primary reproductive axis regulator. The pattern of GnRH, FSH, and LH release is determined by its pulsatile secretion, which in turn controls endocrine function and gamete maturation in the gonads. Peptides called Kisspeptin (KP), Neurokinin-B (NKB), and Orexin influence both positive and negative feedback modulation of GnRH, FSH, and LH secretion in reproduction. This review article mainly focuses on the historical perspective, isoform, and signaling pathways of KP, NKB, and Orexin novel peptide-based targets including clinical and preclinical studies and having a promising effect in the management of infertility.

Tokishakuyakusan alleviates ultraviolet-induced skin pigmentation by decreasing the expression of melanogenesis-related enzymes

Ethnopharmacological relevanceTokishakuyakusan (TSS), a traditional Kampo medicine, can effectively alleviate symptoms unique to women, such as menstrual pain and menopausal symptoms, and this effect is believed to be related to its ability to increase the secretion of female hormones. TSS is also believed to be effective against skin pigmentation. However, no studies have examined the effect of TSS on pigmentation. Aim of the studyIn this study, we conducted basic research to determine the effects of TSS on pigmentation. Materials and MethodsFemale HRM-2 mice were given free access to a normal diet or a TSS-containing diet for 7 weeks. For 3 weeks starting from the 4th week of treatment, the back of the skin was irradiated with ultraviolet (UV) light, and the melanin level was measured. The expression levels of melanogenesis-related genes and inflammatory markers in the skin were analyzed. ResultsThe melanin level in the skin of the mice exposed to UV radiation was approximately three times greater than that in the skin of the mice in the non-UV-irradiated group, confirming pigmentation due to UV irradiation. The protein expression levels of tyrosinase (Tyr), tyrosinase-related protein-1 (Tyrp1), and dopachrome tautomerase (Dct), which are important for melanin production, were significantly greater in the UV irradiation group than in the non-UV irradiation group. In contrast, the amount of skin melanin in the mice treated with TSS was significantly lower than that in the UV-irradiated group, and the expression levels of melanogenesis-related enzymes were also lower. Furthermore, TSS significantly decreased the expression of microphthalmia transcription factor (MITF), a transcription factor for melanogenesis-related enzymes, and the inflammatory cytokines interleukin-1β and interleukin-6. ConclusionsTSS inhibits melanin production in melanocytes by suppressing the increase in the expression of melanogenesis-related enzymes caused by UV irradiation. These findings suggested that this effect of TSS is exerted through the combined regulation of MITF expression and anti-inflammatory responses.

A PACAP-activated network for secretion requires coordination of Ca2+ influx and Ca2+ mobilization.

Chromaffin cells of the adrenal medulla transduce sympathetic nerve activity into stress hormone secretion. The two neurotransmitters principally responsible for coupling cell stimulation to secretion are acetylcholine and pituitary adenylate activating polypeptide (PACAP). In contrast to acetylcholine, PACAP evokes a persistent secretory response from chromaffin cells. However, the mechanisms by which PACAP acts are poorly understood. Here, it is shown that PACAP induces sustained increases in cytosolic Ca2+ which are disrupted when Ca2+ influx through L-type channels is blocked or internal Ca2+ stores are depleted. PACAP liberates stored Ca2+ via inositol trisphosphate receptors (IP3Rs) on the endoplasmic reticulum (ER), thereby functionally coupling Ca2+ mobilization to Ca2+ influx and supporting Ca2+-induced Ca2+-release. These Ca2+ influx and mobilization pathways are unified by an absolute dependence on phospholipase C epsilon (PLCε) activity. Thus, the persistent secretory response that is a defining feature of PACAP activity, in situ, is regulated by a signaling network that promotes sustained elevations in intracellular Ca2+ through multiple pathways.

A Brain Anti-Senescence Transcriptional Program Triggered by Hypothalamic-Derived Exosomal microRNAs.

In contrast to the hypothesis that aging results from cell-autonomous deterioration processes, the programmed longevity theory proposes that aging arises from a partial inactivation of a "longevity program" aimed at maintaining youthfulness in organisms. Supporting this hypothesis, age-related changes in organisms can be reversed by factors circulating in young blood. Concordantly, the endocrine secretion of exosomal microRNAs (miRNAs) by hypothalamic neural stem cells (htNSCs) regulates the aging rate by enhancing physiological fitness in young animals. However, the specific molecular mechanisms through which hypothalamic-derived miRNAs exert their anti-aging effects remain unexplored. Using experimentally validated miRNA-target gene interactions and single-cell transcriptomic data of brain cells during aging and heterochronic parabiosis, we identify the main pathways controlled by these miRNAs and the cell-type-specific gene networks that are altered due to age-related loss of htNSCs and the subsequent decline in specific miRNA levels in the cerebrospinal fluid (CSF). Our bioinformatics analysis suggests that these miRNAs modulate pathways associated with senescence and cellular stress response, targeting crucial genes such as Cdkn2a, Rps27, and Txnip. The oligodendrocyte lineage appears to be the most responsive to age-dependent loss of exosomal miRNA, leading to significant derepression of several miRNA target genes. Furthermore, heterochronic parabiosis can reverse age-related upregulation of specific miRNA-targeted genes, predominantly in brain endothelial cells, including senescence promoting genes such as Cdkn1a and Btg2. Our findings support the presence of an anti-senescence mechanism triggered by the endocrine secretion of htNSC-derived exosomal miRNAs, which is associated with a youthful transcriptional signature.

Histone methylation: at the crossroad between circadian rhythms in transcription and metabolism

Circadian rhythms, essential 24-hour cycles guiding biological functions, synchronize organisms with daily environmental changes. These rhythms, which are evolutionarily conserved, govern key processes like feeding, sleep, metabolism, body temperature, and endocrine secretion. The central clock, located in the suprachiasmatic nucleus (SCN), orchestrates a hierarchical network, synchronizing subsidiary peripheral clocks. At the cellular level, circadian expression involves transcription factors and epigenetic remodelers, with environmental signals contributing flexibility. Circadian disruption links to diverse diseases, emphasizing the urgency to comprehend the underlying mechanisms. This review explores the communication between the environment and chromatin, focusing on histone post-translational modifications. Special attention is given to the significance of histone methylation in circadian rhythms and metabolic control, highlighting its potential role as a crucial link between metabolism and circadian rhythms. Understanding these molecular intricacies holds promise for preventing and treating complex diseases associated with circadian disruption.

The marijuana, cannabinoids, and female reproductive system.

The marijuana is considered as widely used recreational illicit drug that has become popular among women of reproductive age. It is believed that the marijuana use may have negative impacts on the female fertility. However, the exact mechanisms of its reproductive toxicity remain unclear. The studies suggest that the exogenous cannabinoids may interfere with endocannabinoid system and disrupt hypothalamic-pituitary-ovary axis. Consequently, it impacts the female fertility by disruption of normal secretion of ovarian sex hormones and menstrual cycles. However, other studies have shown that medical marijuana is useful analgesic agent for pain management. But, given that the wide range of cannabinoids side effects are reported, it seems that caution should be taken in the recreational use of these substances. In summary, this article aimed to review the possible impacts of marijuana and its derivatives on the main female reproductive organs and embryonic growth and development.

Body Condition in Small Ruminants—Effects of Nutrition on the Hypothalamic–Pituitary–Gonad Axis and Ovarian Activity That Controls Reproduction

Nutritional status plays a vital role in regulating ovary activity. This regulation is mediated by the hypothalamus–pituitary–gonad axis and by effects exerted directly on the ovary. Therefore, to achieve the best reproductive performance, it is essential to know how the nutritional status affects the secretion of GnRH, gonadotrophins, and sex steroid hormones. Adequate body reserves and energy balance are critical for optimal reproductive performance in sheep and goats. However, over- or under-conditioned animals experience issues like extended anestrus, irregular ovarian cycles, and reduced conception. Body condition scoring allows for the evaluation of the relationships between adiposity, nutritional status, and fertility. Acute feed deficits briefly stimulate processes, but chronic restrictions suppress pulsatile LH release, disrupting ovarian function. The process of follicle development is a very complex one which involves intricate interactions between the pituitary gonadotrophins and metabolic hormones as well as between the locally produced factors by the ovarian somatic and germ cells including the IGF system and the TGF-β superfamily members. Genotype and nutrition are factors that have an impact on follicular development, and seasonal factors are also involved. This review will give a brief overview on how the body condition can be evaluated and the effects of nutrition on the hypothalamus–pituitary–gonad axis and ovarian activity, which are responsible for reproductive regulation. This paper presents a clear and reasonable summary of the pathway that runs from the nutritional status of small ruminants to ovarian activity through the hypothalamic–pituitary–gonadal axis. This review summarizes methods for body condition evaluation in small ruminants and evidence regarding acute versus prolonged nutritional impacts on the hypothalamic–pituitary–gonadal axis and ovarian activity controlling reproduction.

Pancreatic neuroendocrine tumors: Are tumors smaller than 2 cm truly indolent?

Pancreatic neuroendocrine tumors (PNETs) are relatively rare but rank as the second most common pancreatic neoplasm. They can be functional, causing early metabolic disturbances due to hormone secretion, or non-functional and diagnosed later based on tumor size-related symptoms. Recent diagnoses of PNETs under 2 cm in size have sparked debates about their management; some practitioners advocate for surgical removal and others suggest observation due to the tumors' lower potential for malignancy. However, it is unclear whether managing these small tumors expectantly is truly safe. To evaluate poor prognostic factors in PNETs based on tumor size (> 2 cm or < 2 cm) in surgically treated patients. This cohort study included 64 patients with PNETs who underwent surgical resection between 2006 and 2019 at a high-complexity reference hospital in Medellín, Colombia. To assess patient survival, quarterly follow-ups were conducted during the first year after surgery, followed by semi-annual consultations at the hospital's hepatobiliary surgery department. Qualitative variables were described using absolute and relative frequencies, and quantitative variables were expressed using measures of central tendency and their corresponding measures of dispersion. The presence of lymph node involvement, neural involvement, and lymphovascular invasion were all associated with an increased risk of mortality, with hazard ratios of 5.68 (95%CI: 1.26-25.61, P = 0.024), 6.44 (95%CI: 1.43-28.93, P = 0.015), and 24.87 (95%CI: 2.98-207.19, P = 0.003), respectively. Neural involvement and lymphovascular invasion were present in tumors smaller than 2 cm in diameter and those larger than 2 cm in diameter. The recurrence rates between the two tumor groups were furthermore similar: 18.2% for tumors smaller than 2 cm and 21.4% for tumors larger than 2 cm. Patient survival was additionally comparable between the two tumor groups. Tumor size does not dictate prognosis; lymph node and lymphovascular involvement affect mortality, which highlights that histopathological factors-rather than tumor size-may play a role in management.

NTRK2 Promotes Sheep Granulosa Cells Proliferation and Reproductive Hormone Secretion and Activates the PI3K/AKT Pathway.

Neurotrophin receptor B (NTRK2), also named TRKB, belongs to the neurotrophic factor family. Previous studies have shown that NTRK2 is associated with high fertility in mammals. However, the molecular mechanism and regulatory pathway of this neurotrophic factor remain unclear. In this study, NTRK2 overexpression and NTRK2-siRNA were constructed to detect the effects of NTRK2 on the proliferation and hormone secretion of the ovarian granulosa cells (GCs) of sheep. We successfully isolated follicular phase granulosa cells in vitro from the ovaries of sheep in simultaneous estrus, and the immunofluorescence results confirmed that NTRK2 was expressed in the collected cells. Subsequently, the effect of NTRK2 on the proliferation of sheep granulosa cells was examined via cell transfection experiments. The results showed that the expression of CDK4 and CyclinD2 was significantly increased after NTRK2 overexpression, while the opposite trend was observed after the inhibition of NTRK2 expression (p < 0.05). The EdU and CCK-8 assays showed that the proliferation rate of sheep GCs was significantly increased after NTRK2 overexpression, while the opposite trend was observed after the inhibition of NTRK2 expression (p < 0.05). Moreover, NTRK2 significantly increased the expression of steroidogenesis-related genes, including steroidogenic acute regulatory protein (STAR) and hydroxy-δ-5-steroid dehydrogenase (HSD3B1), and cytochrome P450 family 19 subfamily A member 1 (CYP19A1). The ELISA results showed that the secretion levels of E2 and P4 significantly increased after NTRK2 overexpression, while the opposite trend was observed after the inhibition of NTRK2 expression (p < 0.05). Previous studies had confirmed that NTRK2 gene belongs to the PI3K-AKT signaling pathway and participates in the signaling of this pathway. This was demonstrated by protein-protein interaction analysis and NTRK2 belongs to the PI3K-AKT pathway. The modification of PI3K and AKT, markers of the PI3K-AKT pathway, via phosphorylation was increased after NTRK2 overexpression in the sheep GCs, while the opposite trend was observed after the inhibition of NTRK2 expression (p < 0.05). Overall, these results suggest that the NTRK2 gene regulates the proliferation of GCs and the secretion of steroid hormones in sheep, and that it influences the phosphorylation level of the PI3K/AKT signaling pathway. These findings provided a theoretical basis and new perspectives for exploring the regulation of NTRK2 gene in the development of ovine follicles.

Curcumin mitigates stress induced depression and hippocampal damage through upregulation of BDNF expression and adult neurogenesis.

Chronic stress, recognized as a major precipitant of depression, has been linked to various neural alterations, including cell death, neuronal atrophy, and compromised hippocampal neurogenesis and plasticity. This study aim to scrutinize curcumin's influence on glucocorticoid hormone secretion and its subsequent effects on the structural integrity and neurogenesis of the hippocampal neurons. A total of 30 adult albino Wistar rats, each weighing between 200-250 g, were utilized for the study. The rats, excluding those in the control group, underwent a 42-day regimen of modified Chronic Unpredictable Stress (CUS) to induce depressive-like states. After inducing CUS, these rats were categorized into six groups, each receiving different oral treatments for two weeks. The treatments included 30 mg/kg body weight of curcumin, 20 mg/kg body weight of fluoxetine, or a combination of both, along with a control group that received distilled water and an olive oil treated group. The rats were tested for behavioural despair using the forced swim test and their blood samples were obtained for serum corticosterone test. Afterwards, the rats were anesthetized, transcardially perfused and the hippocampus dissected and prepared for histopathological study. The study's multi-faceted approach encompassed behavioral, biochemical, and histological evaluations. Behavioral despair, gauged through the forced swimming test, displayed a marked reduction in the curcumin-treated rats compared to controls (p&lt;0.05). Additionally, curcumin significantly lowered serum corticosterone levels, aligning them closely with the control levels. Histomorphological analysis of the hippocampus showed that the curcumin- treated rats exhibited substantially less neurodegeneration, as evidenced by fewer cytoplasmic vacuolations and more intact neuronal structures. Increased cell proliferation and BDNF level were also observed in curcumin treated rats. This study has illuminated a multifaceted approach through which curcumin mitigates hippocampal neurodegeneration, thus showing possible therapeutic potential of curcumin in ameliorating depressive symptoms.