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International Journal of Molecular... Apr 2024Many genomic, anatomical and functional differences exist between the medullary (MTAL) and the cortical thick ascending limb of the loop of Henle (CTAL), including a...
Many genomic, anatomical and functional differences exist between the medullary (MTAL) and the cortical thick ascending limb of the loop of Henle (CTAL), including a higher expression of claudin-10 (CLDN10) in the MTAL than in the CTAL. Therefore, we assessed to what extent the gene expression is a determinant of differential gene expression between MTAL and CTAL. RNAs extracted from CTAL and MTAL microdissected from wild type (WT) and Cldn10 knock out mice (cKO) were analyzed by RNAseq. Differential and enrichment analyses (GSEA) were performed with interactive R Shiny software. Between WT and cKO MTAL, 637 genes were differentially expressed, whereas only 76 were differentially expressed between WT and cKO CTAL. Gene expression patterns and GSEA analyses in all replicates showed that WT MTAL did not cluster with the other replicates; no hierarchical clustering could be found between WT CTAL, cKO CTAL and cKO MTAL. Compared to WT replicates, cKO replicates were enriched in , , , (parathyroid hormone receptor type 1), (calcium sensing receptor) and (Vitamin D Receptor) mRNA in both the cortex and medulla. is associated with gene expression patterns, including genes specifically involved in divalent cations reabsorption in the TAL.
Topics: Animals; Mice; Extremities; Adrenal Medulla; Claudins; Mice, Knockout; Gene Expression
PubMed: 38612818
DOI: 10.3390/ijms25074008 -
Cancers Mar 2024Pheochromocytomas and paragangliomas are rare neuroendocrine tumours that originate from chromaffin cells within the adrenal medulla or extra-adrenal sympathetic...
INTRODUCTION
Pheochromocytomas and paragangliomas are rare neuroendocrine tumours that originate from chromaffin cells within the adrenal medulla or extra-adrenal sympathetic ganglia. Management of disseminated or metastatic pheochromocytomas and paragangliomas continues to pose challenges and relies on limited evidence.
METHOD
In this study, we report retrospective data on median overall survival (OS) and median progression-free survival (PFS) for all Danish patients treated with peptide receptor radionuclide therapy (PRRT) with Lu-Dotatate or Y-Dotatate over the past 15 years. One standard treatment of PRRT consisted of 4 consecutive cycles with 8-14-week intervals.
RESULTS
We included 28 patients; 10 were diagnosed with pheochromocytoma and 18 with paraganglioma. Median age at first PRRT was 47 (IQR 15-76) years. The median follow-up time was 31 (IQR 17-37) months. Eight patients died during follow-up. Median OS was 72 months, and 5-year survival was 65% with no difference between pheochromocytoma and paraganglioma. Patients with germline mutations had better survival than patients without mutations ( = 0.041). Median PFS after the first cycle of PRRT was 30 months. For patients who previously received systemic treatment, the median PFS was 19 months, compared with 32 months for patients with no previous systemic treatment ( = 0.083).
CONCLUSIONS
The median OS of around 6 years and median PFS of around 2.5 years found in this study are comparable to those reported in previous studies employing PRRT. Based on historical data, the efficacy of PRRT may be superior to I-MIBG therapy, and targeted therapy with sunitinib and PRRT might therefore be considered as first-line treatment in this patient group.
PubMed: 38611027
DOI: 10.3390/cancers16071349 -
Role of Serotonylation and SERT Posttranslational Modifications in Alzheimer's Disease Pathogenesis.Aging and Disease Apr 2024The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) is implicated mainly in Alzheimer's disease (AD) and reported to be responsible for several processes and... (Review)
Review
The neurotransmitter serotonin (5-hydroxytryptamine, 5-HT) is implicated mainly in Alzheimer's disease (AD) and reported to be responsible for several processes and roles in the human body, such as regulating sleep, food intake, sexual behavior, anxiety, and drug abuse. It is synthesized from the amino acid tryptophan. Serotonin also functions as a signal between neurons to mature, survive, and differentiate. It plays a crucial role in neuronal plasticity, including cell migration and cell contact formation. Various psychiatric disorders, such as depression, schizophrenia, autism, and Alzheimer's disease, have been linked to an increase in serotonin-dependent signaling during the development of the nervous system. Recent studies have found 5-HT and other monoamines embedded in the nuclei of various cells, including immune cells, the peritoneal mast, and the adrenal medulla. Evidence suggests these monoamines to be involved in widespread intracellular regulation by posttranslational modifications (PTMs) of proteins. Serotonylation is the calcium-dependent process in which 5-HT forms a long-lasting covalent bond to small cytoplasmic G-proteins by endogenous transglutaminase 2 (TGM2). Serotonylation plays a role in various biological processes. The purpose of our article is to summarize historical developments and recent advances in serotonin research and serotonylation in depression, aging, AD, and other age-related neurological diseases. We also discussed several of the latest developments with Serotonin, including biological functions, pathophysiological implications and therapeutic strategies to treat patients with depression, dementia, and other age-related conditions.
PubMed: 38607731
DOI: 10.14336/AD.2024.0328 -
Cureus Mar 2024Pheochromocytomas are neuroendocrine tumors that produce, store, and secrete catecholamines. They are found in the chromaffin tissue of the adrenal medulla and manifest...
Pheochromocytomas are neuroendocrine tumors that produce, store, and secrete catecholamines. They are found in the chromaffin tissue of the adrenal medulla and manifest clinical symptoms by producing an excessive amount of one or more catecholamines, such as dopamine, adrenaline, and noradrenaline, as well as their inactive metabolites, such as metanephrine, normetanephrine, and 3-methoxytyramine. This paper is the case report of a 53-year-old male patient with diabetes and hypertension who has been experiencing symptoms such as night sweats, frequent colds, weight loss, reduced appetite, and generalized anxiety. The patient presented with pelvic pain and sought medical attention, leading to an abdominal MRI scan that revealed a right adrenal mass. The patient's plasma metanephrine levels were found to be four-fold higher than the normal range. A contrast CT scan of the abdomen and pelvis revealed a right adrenal gland with increased dimensions and well-defined edges. A diagnosis of right adrenal pheochromocytoma was made. The patient underwent a right laparoscopic adrenalectomy, which resulted in a reduction in metanephrine levels and normal blood pressure readings. The patient presented a favorable clinical evolution in the post-surgical period, for which it was decided to be discharged home.
PubMed: 38571831
DOI: 10.7759/cureus.55504 -
Cureus Feb 2024Introduction Various studies have linked suicidal behavior, stress, affective disorders, and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis resulting...
Introduction Various studies have linked suicidal behavior, stress, affective disorders, and dysregulation of the hypothalamic-pituitary-adrenal (HPA) axis resulting from chronic stress. Chronic stress has been shown to cause enlargement of the adrenal glands, altering their function and potentially leading to suicidal behaviors in individuals with depression. This study aimed to compare the histological changes in the adrenal glands of individuals who died by suicide with those who experienced sudden death. Suicide victims are exposed to chronic stress, while individuals with sudden deaths face acute stress related to the act of dying. Methods This analytical study, approved by the Institutional Ethics Committee (IEC), was conducted in the Department of Forensic Medicine and Toxicology at Gandhi Medical College, Bhopal. The study included 100 confirmed cases of suicide, irrespective of gender, aged 15-60 years, with notable autopsy findings, relevant history, no signs of decomposition, and varying survival periods (including immediate deaths within 24 hours). Additionally, 20 controls were selected, involving individuals who died suddenly from causes other than suicide within 24 hours of the incident. Informed consent was obtained using a prescribed proforma from relatives and the police. Histological examination slides of the adrenals were prepared and analyzed. Data were collected and statistically analyzed using GraphPad software and Epi Info 7. Results Capsular hemorrhage was observed in 98% of suicide cases and 40% of controls. Nodulation was present in 48% of suicidal cases and 20% of controls. Zonal extension of zona fasciculata was specific to chronic stress in suicidal cases. In 25% of suicidal cases, a prominent extension of the medulla was noted. Irregular thinning of zona glomerulosa with shrunken cells and increased nuclear density in 88% of cases were considered specific to chronic stress conditions and suicide, not observed in controls. Lipid depletion was observed in all suicidal cases, with diffuse depletion in 47% and focal depletion in 53% of cases. In contrast, 45% of those exposed to the acute stress of dying showed focal depletion, with none exhibiting diffuse depletion. Suicidal cases displayed dilated prominent sinusoids in all three zones and the adrenal medulla (98-99%), absent in controls. Adrenal hemorrhage and necrosis were specific to chronic stress conditions, with 7%, 8%, 32%, and 16% of cases showing hemorrhage in all three zones and adrenal medulla, respectively, and none in controls. Conclusion Histological changes observed in acute stress conditions included focal lipid depletion, capsular hemorrhage, nodular hyperplasia, and hemorrhage and necrosis with edema. However, the proportion and severity of these changes were lower than those observed in the suicidal group, suggesting that these findings may be considered non-specific for differentiating between acute and chronic stress.
PubMed: 38523945
DOI: 10.7759/cureus.54630 -
Frontiers in Endocrinology 2024Maternal diabetes is a recognized risk factor for both short-term and long-term complications in offspring. Beyond the direct teratogenicity of maternal diabetes, the...
INTRODUCTION
Maternal diabetes is a recognized risk factor for both short-term and long-term complications in offspring. Beyond the direct teratogenicity of maternal diabetes, the intrauterine environment can influence the offspring's cardiovascular health. Abnormalities in the cardiac sympathetic system are implicated in conditions such as sudden infant death syndrome, cardiac arrhythmic death, heart failure, and certain congenital heart defects in children from diabetic pregnancies. However, the mechanisms by which maternal diabetes affects the development of the cardiac sympathetic system and, consequently, heightens health risks and predisposes to cardiovascular disease remain poorly understood.
METHODS AND RESULTS
In the mouse model, we performed a comprehensive analysis of the combined impact of a -deficient sympathetic system and the maternal diabetes environment on both heart development and the formation of the cardiac sympathetic system. The synergic negative effect of exposure to maternal diabetes and deficiency resulted in the most pronounced deficit in cardiac sympathetic innervation and the development of the adrenal medulla. Abnormalities in the cardiac sympathetic system were accompanied by a smaller heart, reduced ventricular wall thickness, and dilated subepicardial veins and coronary arteries in the myocardium, along with anomalies in the branching and connections of the main coronary arteries. Transcriptional profiling by RNA sequencing (RNA-seq) revealed significant transcriptome changes in -deficient sympathetic neurons, primarily associated with cell cycle regulation, proliferation, and mitosis, explaining the shrinkage of the sympathetic neuron population.
DISCUSSION
Our data demonstrate that a failure to adequately activate the HIF-1α regulatory pathway, particularly in the context of maternal diabetes, may contribute to abnormalities in the cardiac sympathetic system. In conclusion, our findings indicate that the interplay between deficiencies in the cardiac sympathetic system and subtle structural alternations in the vasculature, microvasculature, and myocardium during heart development not only increases the risk of cardiovascular disease but also diminishes the adaptability to the stress associated with the transition to extrauterine life, thus increasing the risk of neonatal death.
Topics: Animals; Child; Female; Humans; Infant, Newborn; Mice; Pregnancy; Cardiovascular Diseases; Diabetes, Gestational; Heart; Heart Failure; Myocardium; Hypoxia-Inducible Factor 1, alpha Subunit
PubMed: 38505753
DOI: 10.3389/fendo.2024.1344074 -
European Heart Journal. Case Reports Mar 2024Tumour-producing catecholamines arise in the adrenal medulla (pheochromocytomas), as well as in extra-adrenal chromaffin cells (paragangliomas). The origin can be from...
BACKGROUND
Tumour-producing catecholamines arise in the adrenal medulla (pheochromocytomas), as well as in extra-adrenal chromaffin cells (paragangliomas). The origin can be from any location; however, it is very rare in the heart.
CASE SUMMARY
A 43-year-old woman with a history of arterial hypertension presented with dyspnoea on moderate exertion, New York Class Association (NYHA) functional classes III and IV, and oedema in the lower extremities. Medical and laboratory evaluation revealed an NT-proBNP of 6046 pg/mL, a left ventricular ejection fraction (LVEF) of 15%, longitudinal strain of -7%, and a mass located on the inner surface of the left atrioventricular groove. Surgical intervention was performed, and the tumour was resected. Pathological report showed an extra-adrenal paraganglioma without neoplastic involvement in the margins of the vena cava. After surgery, the patient showed clinical improvement with NYHA functional class I, LVEF of 56%, and longitudinal strain of -20% on transthoracic echocardiography 4 months after treatment.
DISCUSSION
Paragangliomas are tumours that are rarely found in the heart, and their diagnosis is difficult. However, early detection and treatment can improve the quality of life of affected patients.
PubMed: 38496798
DOI: 10.1093/ehjcr/ytae032 -
Journal of Zhejiang University.... Mar 2024Pheochromocytomas and paragangliomas (PPGLs) cause symptoms by altering the circulation levels of catecholamines and peptide hormones. Currently, the diagnosis of PPGLs...
Pheochromocytomas and paragangliomas (PPGLs) cause symptoms by altering the circulation levels of catecholamines and peptide hormones. Currently, the diagnosis of PPGLs relies on diagnostic imaging and the detection of catecholamines. In this study, we used ultra-performance liquid chromatography (UPLC)/quadrupole time-of-flight mass spectrometry (Q-TOF MS) analysis to identify and measure the perioperative differential metabolites in the plasma of adrenal pheochromocytoma patients. We identified differentially expressed genes by comparing the transcriptomic data of pheochromocytoma with the normal adrenal medulla. Through conducting two steps of metabolomics analysis, we identified 111 differential metabolites between the healthy group and the patient group, among which 53 metabolites were validated. By integrating the information of differential metabolites and differentially expressed genes, we inferred that the cysteine-methionine, pyrimidine, and tyrosine metabolism pathways were the three main metabolic pathways altered by the neoplasm. The analysis of transcription levels revealed that the tyrosine and cysteine-methionine metabolism pathways were downregulated in pheochromocytoma, whereas the pyrimidine pathway showed no significant difference. Finally, we developed an optimized diagnostic model of two metabolites, L-dihydroorotic acid and vanylglycol. Our results for these metabolites suggest that they may serve as potential clinical biomarkers and can be used to supplement and improve the diagnosis of pheochromocytoma.
PubMed: 38448048
DOI: 10.1631/jzus.B2300579 -
Endocrine Pathology Mar 2024Hand2 is a core transcription factor responsible for chromaffin cell differentiation. However, its potential utility in surgical pathology has not been studied. Thus, we...
Hand2 is a core transcription factor responsible for chromaffin cell differentiation. However, its potential utility in surgical pathology has not been studied. Thus, we aimed to investigate its expression in paragangliomas, other neuroendocrine neoplasms (NENs), and additional non-neuroendocrine tumors. We calibrated Hand2 immunohistochemistry on adrenal medulla cells and analyzed H-scores in 46 paragangliomas (PGs), 9 metastatic PGs, 21 cauda equina neuroendocrine tumors (CENETs), 48 neuroendocrine carcinomas (NECs), 8 olfactory neuroblastomas (ONBs), 110 well-differentiated NETs (WDNETs), 10 adrenal cortical carcinomas, 29 adrenal cortical adenomas, 8 melanomas, 41 different carcinomas, and 10 gastrointestinal stromal tumors (GISTs). Both tissue microarrays (TMAs) and whole sections (WSs) were studied. In 171 NENs, previously published data on Phox2B and GATA3 were correlated with Hand2. Hand2 was positive in 98.1% (54/55) PGs, but only rarely in WDNETs (9.6%, 10/104), CENETs (9.5%, 2/21), NECs (4.2%, 2/48), or ONBs (12.5%, 1/8). Any Hand2 positivity was 98.1% sensitive and 91.7% specific for the diagnosis of PG. The Hand2 H-score was significantly higher in primary PGs compared to Hand2-positive WDNETs (median 166.3 vs. 7.5; p < 0.0001). Metastatic PGs were positive in 88.9% (8/9). No Hand2 positivity was observed in any adrenal cortical neoplasm or other non-neuroendocrine tumors, with exception of 8/10 GISTs. Parasympathetic PGs showed a higher Hand2 H-score compared to sympathetic PGs (median H-scores 280 vs. 104, p < 0.0001). Hand2 positivity in NENs serves as a reliable marker of primary and metastatic PG, since other NENs only rarely exhibit limited Hand2 positivity.
Topics: Humans; Immunohistochemistry; Neuroendocrine Tumors; Transcription Factors; Paraganglioma; Carcinoma, Neuroendocrine
PubMed: 38416360
DOI: 10.1007/s12022-024-09803-6