-
International Journal of Molecular... May 2024Sympathetic nervous system (SNS) hyperactivity is mediated by elevated catecholamine (CA) secretion from the adrenal medulla, as well as enhanced norepinephrine (NE)...
Sympathetic nervous system (SNS) hyperactivity is mediated by elevated catecholamine (CA) secretion from the adrenal medulla, as well as enhanced norepinephrine (NE) release from peripheral sympathetic nerve terminals. Adrenal CA production from chromaffin cells is tightly regulated by sympatho-inhibitory α-adrenergic (auto)receptors (ARs), which inhibit both epinephrine (Epi) and NE secretion via coupling to Gi/o proteins. α-AR function is, in turn, regulated by G protein-coupled receptor (GPCR)-kinases (GRKs), especially GRK2, which phosphorylate and desensitize them, i.e., uncouple them from G proteins. On the other hand, the short-chain free fatty acid (SCFA) receptor (FFAR)-3, also known as GPR41, promotes NE release from sympathetic neurons via the Gi/o-derived free Gβγ-activated phospholipase C (PLC)-β/Ca signaling pathway. However, whether it exerts a similar effect in adrenal chromaffin cells is not known at present. In the present study, we examined the interplay of the sympatho-inhibitory α-AR and the sympatho-stimulatory FFAR3 in the regulation of CA secretion from rat adrenal chromaffin (pheochromocytoma) PC12 cells. We show that FFAR3 promotes CA secretion, similarly to what GRK2-dependent α-AR desensitization does. In addition, FFAR3 activation enhances the effect of the physiologic stimulus (acetylcholine) on CA secretion. Importantly, GRK2 blockade to restore α-AR function or the ketone body beta-hydroxybutyrate (BHB or 3-hydroxybutyrate), via FFAR3 antagonism, partially suppress CA production, when applied individually. When combined, however, CA secretion from PC12 cells is profoundly suppressed. Finally, propionate-activated FFAR3 induces leptin and adiponectin secretion from PC12 cells, two important adipokines known to be involved in tissue inflammation, and this effect of FFAR3 is fully blocked by the ketone BHB. In conclusion, SCFAs can promote CA and adipokine secretion from adrenal chromaffin cells via FFAR3 activation, but the metabolite/ketone body BHB can effectively inhibit this action.
Topics: Animals; PC12 Cells; Rats; Receptors, G-Protein-Coupled; Catecholamines; Receptors, Adrenergic, alpha-2; Adipokines; Chromaffin Cells; Signal Transduction; Norepinephrine
PubMed: 38791266
DOI: 10.3390/ijms25105227 -
Neurochemistry International May 2024Transient global cerebral ischemia (GCI) results in delayed neuronal death, primarily apoptosis, in the hippocampal CA1 subregion, which leads to severe cognitive...
Transient global cerebral ischemia (GCI) results in delayed neuronal death, primarily apoptosis, in the hippocampal CA1 subregion, which leads to severe cognitive deficits. While therapeutic hypothermia is an approved treatment for patients following cardiac arrest, it is associated with various adverse effects. Secretoneurin (SN) is an evolutionarily conserved neuropeptide generated in the brain, adrenal medulla and other endocrine tissues. In this study, SN was infused into the rat brain by intracerebroventricular injection 1 day after GCI, and we demonstrated that SN could significantly preserve spatial learning and memory in the Barnes maze tasks examined on days 14-17 after GCI. To further investigate underlying pathways involved, we demonstrated that, on day 5 after GCI, SN could significantly inhibit GCI-induced expression levels of Apoptosis Inducing Factor (AIF) and cleaved-PARP1, as well as neuronal apoptosis and synaptic loss in the hippocampal CA1 region. Additionally, SN could attenuate GCI-induced activation of both caspase-1 and caspase-3, and the levels of pro-inflammatory cytokines IL-1β and IL-18 in the CA1 region. Mechanically, we observed that treatment with SN effectively inhibited NLRP3 protein elevation and the bindings of NLRP3-ASC and ASC-caspase-1 in hippocampal neurons after GCI. In summary, our data indicate that SN could effectively attenuate NLRP3 inflammasome formation, as well as the activation of caspase-1 and -3, the production of pro-inflammatory cytokines, and ultimately the neuronal apoptotic loss induced by GCI. Potential neuronal pyroptosis, or caspase-1-dependent cell death, could also be involved in ischemic neuronal death, which needs further investigation.
PubMed: 38761854
DOI: 10.1016/j.neuint.2024.105770 -
Molecular Biology of the Cell Jul 2024Chromaffin cells of the adrenal medulla transduce sympathetic nerve activity into stress hormone secretion. The two neurotransmitters principally responsible for...
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 Ca which are disrupted when Ca influx through L-type channels is blocked or internal Ca stores are depleted. PACAP liberates stored Ca via inositol trisphosphate receptors (IP3Rs) on the endoplasmic reticulum (ER), thereby functionally coupling Ca mobilization to Ca influx and supporting Ca-induced Ca-release. These Ca 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 Ca through multiple pathways.
Topics: Pituitary Adenylate Cyclase-Activating Polypeptide; Animals; Calcium; Calcium Signaling; Endoplasmic Reticulum; Inositol 1,4,5-Trisphosphate Receptors; Chromaffin Cells; Cattle; Calcium Channels, L-Type
PubMed: 38758660
DOI: 10.1091/mbc.E24-02-0083 -
Radiology Case Reports Aug 2024Adrenal schwannoma is a rare tumor of Schwann cell origin that represents less than 0.2% of all adrenal tumors. These typically benign tumors are most often found in the...
Adrenal schwannoma is a rare tumor of Schwann cell origin that represents less than 0.2% of all adrenal tumors. These typically benign tumors are most often found in the head, neck, and limbs. However, schwannomas can also rarely occur rarely in the adrenal gland within the retroperitoneal cavity. In the adrenal gland, these tumors arise from the medulla and are difficult to diagnose, often misdiagnosed as other benign or malignant entities. In this article, we report the case of a 43-year-old female with a large left adrenal mass revealed by biopsy to be a schwannoma. We focus on the use of radiological imaging modalities and immunohistochemical analysis to optimize diagnosis and treatment intervention of this rare tumor.
PubMed: 38741689
DOI: 10.1016/j.radcr.2024.04.036 -
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.
Topics: Pheochromocytoma; Humans; Adrenal Gland Neoplasms; Pyrimidines; Methionine; Tyrosine; Cysteine; Male; Metabolomics; Female; Middle Aged; Adult; Metabolic Networks and Pathways
PubMed: 38725340
DOI: 10.1631/jzus.B2300579 -
Case Reports in Oncological Medicine 2024Paragangliomas are rare neuroendocrine tumors that arise from the paraganglia, which are clusters of neuroendocrine cells associated with the autonomic nervous system....
Paragangliomas are rare neuroendocrine tumors that arise from the paraganglia, which are clusters of neuroendocrine cells associated with the autonomic nervous system. These tumors are commonly found in the adrenal medulla but can also occur in other locations outside the adrenal gland. Here, we present a case report of a slow-growing paraganglioma in the left neck with spinal metastasis in a 60-year-old man. This case highlights the importance of considering paraganglion tumors in the differential diagnosis of neck masses and the need for early diagnosis and management to prevent potential complications. Importantly, both the clinical picture and anatomical location of these tumors is important when determining treatment plans.
PubMed: 38706789
DOI: 10.1155/2024/2025115 -
Biochemical and Biophysical Research... Jun 2024Orthostatic hypotension (OH) is a common condition. Many potential etiologies of OH have been identified, but in clinical practice the underlying cause of OH is often...
Orthostatic hypotension (OH) is a common condition. Many potential etiologies of OH have been identified, but in clinical practice the underlying cause of OH is often unknown. In the present study, we identified a novel and extraordinary etiology of OH. We describe a first case of acquired severe OH with syncope, and the female patient had extremely low levels of catecholamines and serotonin in plasma, urine and cerebrospinal fluid (CSF). Her clinical and biochemical evidence showed a deficiency of the enzyme aromatic l-amino acid decarboxylase (AADC), which converts l-DOPA to dopamine, and 5-hydroxytryptophan to serotonin, respectively. The consequence of pharmacologic stimulation of catecholaminergic nerves and radionuclide examination revealed her catecholaminergic nerves denervation. Moreover, we found that the patient's serum showed presence of autoantibodies against AADC, and that isolated peripheral blood mononuclear cells (PBMCs) from the patient showed cytokine-induced toxicity against AADC. These observations suggest that her autoimmunity against AADC is highly likely to cause toxicity to adrenal medulla and catecholaminergic nerves which contain AADC, resulting in hypocatecholaminemia and severe OH. Administration of vitamin B6, an essential cofactor of AADC, enhanced her residual AADC activity and drastically improved her symptoms. Our data thus provide a new insight into pathogenesis and pathophysiology of OH.
Topics: Female; Humans; Middle Aged; Aromatic-L-Amino-Acid Decarboxylases; Autoantibodies; Autoimmunity; Catecholamines; Dopamine; Hypotension, Orthostatic; Serotonin
PubMed: 38677008
DOI: 10.1016/j.bbrc.2024.149940 -
Endocrine-related Cancer Jun 2024Pheochromocytoma and paragangliomas (PPGLs) originate from the chromaffin cells of the adrenal medulla or neural crest progenitors outside the adrenal gland,...
Pheochromocytoma and paragangliomas (PPGLs) originate from the chromaffin cells of the adrenal medulla or neural crest progenitors outside the adrenal gland, respectively. The estimated annual incidence of PPGL is between 2.0 and 8.0/million adults. Minimal data exist on the impact of PPGL from the patient's perspective. Therefore, a survey was adapted from a previously published study on gastroenteropancreatic neuroendocrine tumors to explore the voice of patients with PPGL and learn ways to improve clinical care while understanding the current gaps to direct future research. A self-reported online survey was available to patients with PPGL and those with genetic predisposition even without PPGL from June to July 2022. Survey questions captured sociodemographic and clinical characteristics, the diagnostic workup, treatment and monitoring, quality and access to care, and financial impact. Here, we report the most relevant findings on patient experience of disease burden following diagnosis. A total of 270 people responded, the majority of whom were from the USA (79%), Caucasian (88%), and female (81%). The results of this survey highlight the burden of disease on a patient's daily life, resulting in moderate to severe financial distress, increased travel time to specialized facilities resulting in loss of work and wages, and significant delays in care. Respondents reported being unheard and unacknowledged. With a median time to diagnosis just over 2 years, the physical, mental, and emotional toll are substantial. Increasing access to PPGL specialists and centers could lead to faster diagnoses and better management, which may reduce the burden on both patients and healthcare centers.
Topics: Humans; Pheochromocytoma; Female; Adrenal Gland Neoplasms; Male; Paraganglioma; Adult; Middle Aged; Aged; Cost of Illness; Young Adult; Adolescent; Patient Reported Outcome Measures; Surveys and Questionnaires
PubMed: 38657661
DOI: 10.1530/ERC-23-0349 -
Neuroendocrinology 2024
Topics: Animals; Chromaffin Cells; History, 20th Century; Adrenal Medulla; Humans; History, 21st Century
PubMed: 38626738
DOI: 10.1159/000538302 -
Neurosurgical Focus: Video Apr 2024Ganglioneuroma (GN) is a rare solid neoplasm developing from neural crest cells of sympathetic ganglia or adrenal medulla. It usually presents as an asymptomatic mass in...
Ganglioneuroma (GN) is a rare solid neoplasm developing from neural crest cells of sympathetic ganglia or adrenal medulla. It usually presents as an asymptomatic mass in the retroperitoneal space and mediastinum. Resection through open surgery or minimal access is recommended. The video illustrates the case of a 23-year-old female with an incidental finding of thoracic GN. The authors performed a combined, staged approach to ensure complete resection, which involved unilateral T3-4 biportal endoscopy (UBE) for rhizotomy and nerve root decompression, followed by video-assisted thoracoscopic surgery (VATS) for complete excision. The procedure was uneventful, with full recovery and no postoperative complications. The video can be found here: https://stream.cadmore.media/r10.3171/2024.2.FOCVID23210.
PubMed: 38616900
DOI: 10.3171/2024.2.FOCVID23210