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Virchows Archiv : An International... Feb 2022Common to neuroendocrine neoplasms of the pancreas is their expression of synaptophysin, chromogranin A, and/or INSM1. They differ, however, in their histological... (Review)
Review
Common to neuroendocrine neoplasms of the pancreas is their expression of synaptophysin, chromogranin A, and/or INSM1. They differ, however, in their histological differentiation and molecular profile. Three groups can be distinguished: well-differentiated neuroendocrine neoplasms (neuroendocrine tumors), poorly differentiated neuroendocrine neoplasms (neuroendocrine carcinomas), and mixed neuroendocrine-non-neuroendocrine neoplasms. However, the expression of synaptophysin and, to a lesser extent, also chromogranin A is not restricted to the neuroendocrine neoplasms, but may also be in a subset of non-neuroendocrine epithelial and non-epithelial neoplasms. This review provides the essential criteria for the diagnosis of pancreatic neuroendocrine neoplasms including diagnostic clues for the distinction of high-grade neuroendocrine tumors from neuroendocrine carcinomas and an algorithm avoiding diagnostic pitfalls in the delineation of non-neuroendocrine neoplasms with neuroendocrine features from pancreatic neuroendocrine neoplasms.
Topics: Biomarkers, Tumor; Carcinoma, Neuroendocrine; Chromogranin A; Humans; Immunohistochemistry; Neuroendocrine Tumors; Pancreas; Pancreatic Neoplasms; Repressor Proteins; Synaptophysin
PubMed: 34647171
DOI: 10.1007/s00428-021-03211-5 -
Aging May 2020The lemon essential oil (LEO), extracted from the fruit of lemon, has been used to treat multiple pathological diseases, such as diabetes, inflammation, cardiovascular...
The lemon essential oil (LEO), extracted from the fruit of lemon, has been used to treat multiple pathological diseases, such as diabetes, inflammation, cardiovascular diseases, depression and hepatobiliary dysfunction. The study was designed to study the effects of LEO on cognitive dysfunction induced by Alzheimer's disease (AD). We used APP/PS1 double transgene (APP/PS1) AD mice in the experiment; these mice exhibit significant deficits in synaptic density and hippocampal-dependent spatial related memory. The effects of LEO on learning and memory were examined using the Morris Water Maze (MWM) test, Novel object recognition test, and correlative indicators, including a neurotransmitter (acetylcholinesterase, AChE), a nerve growth factor (brain-derived neurotrophic factor, BDNF), a postsynaptic marker (PSD95), and presynaptic markers (synapsin-1, and synaptophysin), in APP/PS1 mice. Histopathology was performed to estimate the effects of LEO on AD mice. A significantly lowered brain AChE depression in APP/PS1 and wild-type C57BL/6L (WT) mice. PSD95/ Synaptophysin, the index of synaptic density, was noticeably improved in histopathologic changes. Hence, it can be summarized that memory-enhancing activity might be associated with a reduction in the AChE levels and is elevated by BDNF, PSD95, and synaptophysin through enhancing synaptic plasticity.
Topics: Acetylcholinesterase; Alzheimer Disease; Amyloid beta-Peptides; Animals; Behavior, Animal; Brain-Derived Neurotrophic Factor; Cognition; Cognitive Dysfunction; Disease Models, Animal; Disks Large Homolog 4 Protein; Hippocampus; Male; Maze Learning; Mice; Mice, Inbred C57BL; Mice, Transgenic; Morris Water Maze Test; Neuronal Plasticity; Neuroprotective Agents; Oils, Volatile; Plant Oils; Spatial Memory
PubMed: 32392535
DOI: 10.18632/aging.103179 -
FEBS Letters Sep 2023Evidence from biochemistry, genetics, and electron microscopy strongly supports the idea that a ring of Synaptotagmin is central to the clamping and release of synaptic... (Review)
Review
Evidence from biochemistry, genetics, and electron microscopy strongly supports the idea that a ring of Synaptotagmin is central to the clamping and release of synaptic vesicles (SVs) for synchronous neurotransmission. Recent direct measurements in cell-free systems suggest there are 12 SNAREpins in each ready-release vesicle, consisting of six peripheral and six central SNAREpins. The six central SNAREpins are directly bound to the Synaptotagmin ring, are directly released by Ca , and they initially open the fusion pore. The six peripheral SNAREpins are indirectly bound to the ring, each linked to a central SNAREpin by a bridging molecule of Complexin. We suggest that the primary role of peripheral SNAREpins is to provide additional force to 'turbocharge' neurotransmitter release, explaining how it can occur much faster than other forms of membrane fusion. The SV protein Synaptophysin forms hexamers that bear two copies of the v-SNARE VAMP at each vertex, one likely assembling into a peripheral SNAREpin and the other into a central SNAREpin.
Topics: Biological Transport; Cell-Free System; Head; Synaptic Transmission; Synaptotagmins
PubMed: 37643878
DOI: 10.1002/1873-3468.14718 -
Journal of Thoracic Oncology : Official... Jan 2022A new molecular subtype classification was recently proposed for SCLC. It is necessary to validate it in primary SCLC tumors by immunohistochemical (IHC) staining and...
INTRODUCTION
A new molecular subtype classification was recently proposed for SCLC. It is necessary to validate it in primary SCLC tumors by immunohistochemical (IHC) staining and define its clinical relevance.
METHODS
We used IHC to assess four subtype markers (ASCL1, NEUROD1, POU2F3, and YAP1) in 194 cores from 146 primary SCLC tumors. The profiles of tumor-associated CD3 and CD8 T-cells, MYC paralogs, SLFN11, and SYP were compared among different subtypes. Validation was performed using publicly available RNA sequencing data of SCLC.
RESULTS
ASCL1, NEUROD1, POU2F3, and YAP1 were the dominant molecular subtypes in 78.2%, 5.6%, 7%, and 2.8% of the tumors, respectively; 6.3% of the tumors were negative for all four subtype markers. Notably, three cases were uniquely positive for YAP1. Substantial intratumoral heterogeneity was observed, with 17.6% and 2.8% of the tumors being positive for two and three subtype markers, respectively. The non-ASCL1/NEUROD1 tumors had more CD8 T-cells and manifested more frequently an "inflamed" immunophenotype. L-MYC and MYC were more often associated with ASCL1/NEUROD1 subtypes and non-ASCL1/NEUROD1 subtypes, respectively. SLFN11 expression was absent in 40% of the tumors, especially those negative for the four subtype markers. SYP was often expressed in the ASCL1 and NEUROD1 subtypes and was associated with less tumor-associated CD8 T-cells and a "desert" immunophenotype.
CONCLUSIONS
We validated the new molecular subtype classification in primary SCLC tumors by IHC and identified several intriguing associations between subtypes and therapeutic markers. The new subtype classification may potentially assist treatment decisions in SCLC.
Topics: Basic Helix-Loop-Helix Transcription Factors; CD8-Positive T-Lymphocytes; Cell Line, Tumor; Gene Expression Regulation, Neoplastic; Humans; Lung Neoplasms; Neuroendocrine Tumors; Nuclear Proteins; Octamer Transcription Factors; Small Cell Lung Carcinoma; Synaptophysin; YAP-Signaling Proteins
PubMed: 34534680
DOI: 10.1016/j.jtho.2021.08.763 -
International Journal of Molecular... Aug 2020Diabetic retinopathy (DR) is one of the leading causes of blindness globally. Retinal neuronal abnormalities occur in the early stage in DR. Therefore, maintaining...
Diabetic retinopathy (DR) is one of the leading causes of blindness globally. Retinal neuronal abnormalities occur in the early stage in DR. Therefore, maintaining retinal neuronal activity in DR may prevent vision loss. Previously, pemafibrate, a novel selective peroxisome proliferator-activated receptor alpha modulator, was suggested as a promising drug in hypertriglyceridemia. However, the role of pemafibrate remains obscure in DR. Therefore, we aimed to unravel systemic and retinal changes by pemafibrate in diabetes. Adult mice were intraperitoneally injected with streptozotocin (STZ) to induce diabetes. After STZ injection, diet supplemented with pemafibrate was given to STZ-induced diabetic mice for 12 weeks. During the experiment period, body weight and blood glucose levels were examined. Electroretinography was performed to check the retinal neural function. After sacrifice, the retina, liver, and blood samples were subjected to molecular analyses. We found pemafibrate mildly improved blood glucose level as well as lipid metabolism, boosted liver function, increased serum fibroblast growth factor21 level, restored retinal functional deficits, and increased retinal synaptophysin protein expression in STZ-induced diabetic mice. Our present data suggest a promising pemafibrate therapy for the prevention of early DR by improving systemic metabolism and protecting retinal function.
Topics: Animals; Benzoxazoles; Blood Glucose; Body Weight; Butyrates; Diabetes Mellitus, Experimental; Diabetic Retinopathy; Disease Models, Animal; Electroretinography; Fibroblast Growth Factors; Gene Expression Regulation; Lipid Metabolism; Liver Function Tests; Male; Mice; Retina; Streptozocin; Synaptophysin; Treatment Outcome
PubMed: 32872333
DOI: 10.3390/ijms21176243 -
Life Sciences Nov 2023Menopause is a natural process in women that can lead to post-menopausal syndrome with symptoms such as hot flushes, weight gain, anxiety, cognitive decline, and...
AIMS
Menopause is a natural process in women that can lead to post-menopausal syndrome with symptoms such as hot flushes, weight gain, anxiety, cognitive decline, and depression. Hormonal replacement therapy is commonly prescribed. However, it has serious adverse effects. Herbal medicinal products and isoflavones are used as alternatives. D-Pinitol found in Pinaceae and Fabaceae families has anti-inflammatory and antioxidant effects. However, it has not received as much attention as isoflavones. In this study, we investigated whether D-pinitol could alleviate post-menopausal symptoms using an ovariectomized (OVX) mouse model.
MAIN METHODS
Female ICR mice were divided into six groups: sham (vehicle), OVX (vehicle), OVX + D-pinitol (10, 30, 100 mg/kg, p.o.), and OVX + estradiol (0.5 mg/kg, s.c.). Treatment with vehicle, D-pinitol, and estradiol began at seven weeks post ovariectomy. We employed several behavioral tests, hot-flush test, and Western blot analysis.
KEY FINDINGS
We found that D-pinitol treatment (30, 100 mg/kg, p.o.) reversed cognitive dysfunction in OVX mice (novel object recognition and Y-maze test). Additionally, D-pinitol alleviated anxiety-like behaviors (elevated plus-maze) and reversed depressive-like behaviors (splash test, tail suspension test). It also normalized increased basal tail skin temperature in OVX mice. Moreover, D-pinitol administration reversed decreased expression of ERβ and synaptophysin and phosphorylation of ERK and PI3K-Akt-GSK-3β induced by OVX in the hippocampus and prefrontal cortex.
SIGNIFICANCE
These findings indicate that D-pinitol might be a promising candidate for treating post-menopausal symptoms by increasing ERβ and synaptophysin expression levels and activation of ERK or PI3K-Akt-GSK-3β signaling pathway, at least in part.
Topics: Humans; Mice; Female; Animals; Postmenopause; Glycogen Synthase Kinase 3 beta; Synaptophysin; Proto-Oncogene Proteins c-akt; Estrogen Receptor beta; Phosphatidylinositol 3-Kinases; Mice, Inbred ICR; Estradiol; Isoflavones; Ovariectomy
PubMed: 37802198
DOI: 10.1016/j.lfs.2023.122147 -
The American Surgeon Aug 2022Breast primary neuroendocrine tumors (BNETs) are rare, making up less than 1% of all breast carcinoma diagnosis. Their detection relies on physical exams and...
Breast primary neuroendocrine tumors (BNETs) are rare, making up less than 1% of all breast carcinoma diagnosis. Their detection relies on physical exams and mammography. Diagnosis of primary BNET requires findings of no other source of neuroendocrine tumor (eg, pancreatic, lung, and appendix). Histopathologically, they typically stain positive for chromogranin A and/or synaptophysin, as do most neuroendocrine tumors. Currently, there are no agreed upon and standardized treatment protocols as it is a rare diagnosis. Treatment protocols are often built on anecdotal evidence and small case reports and series. Here we discuss a case of BNET in a 51-year-old female and discuss commonly encountered treatment protocols.
Topics: Biomarkers, Tumor; Breast Neoplasms; Carcinoma, Neuroendocrine; Female; Humans; Mammography; Middle Aged; Neuroendocrine Tumors; Synaptophysin
PubMed: 35333626
DOI: 10.1177/00031348221086781 -
Autopsy & Case Reports 2021Paragangliomas are rare, encapsulated, benign neuroendocrine tumors that can arise from the adrenal medulla or extra-adrenal paraganglia. Extra-adrenal paragangliomas...
Paragangliomas are rare, encapsulated, benign neuroendocrine tumors that can arise from the adrenal medulla or extra-adrenal paraganglia. Extra-adrenal paragangliomas may develop a gangliocytic component with ganglion cells (Gangliocytic paragangliomas). Nearly 25%of cauda equina paragangliomas are gangliocytic paragangliomas. Here, we describe the case of a 35-year-old male who presented with weakness of both lower limbs over the last two months. Radiological findings were suggestive of myxopapillary ependymoma. However, the histopathological examination revealed a tumor with cells arranged in sheets, papillae, lobules, and around vessels forming pseudo rosettes. Ganglion cells were seen in small groups and, also singly. Tumor cells were immunopositive for chromogranin, synaptophysin, and S-100. Ganglion cells were immunopositive for synaptophysin, NSE, and NFP. A final histological diagnosis of Gangliocytic paraganglioma (WHO grade I) was made. To date, only nine gangliocytic paraganglioma cases have been previously reported, and to the best of our knowledge, this is the largest gangliocytic paraganglioma.
PubMed: 34307231
DOI: 10.4322/acr.2021.277 -
The Journal of Cell Biology Feb 2022Astrocyte reactivity can directly modulate nervous system function and immune responses during disease and injury. However, the consequence of human astrocyte reactivity...
Astrocyte reactivity can directly modulate nervous system function and immune responses during disease and injury. However, the consequence of human astrocyte reactivity in response to specific contexts and within neural networks is obscure. Here, we devised a straightforward bioengineered neural organoid culture approach entailing transcription factor-driven direct differentiation of neurons and astrocytes from human pluripotent stem cells combined with genetically encoded tools for dual cell-selective activation. This strategy revealed that Gq-GPCR activation via chemogenetics in astrocytes promotes a rise in intracellular calcium followed by induction of immediate early genes and thrombospondin 1. However, astrocytes also undergo NF-κB nuclear translocation and secretion of inflammatory proteins, correlating with a decreased evoked firing rate of cocultured optogenetic neurons in suboptimal conditions, without overt neurotoxicity. Altogether, this study clarifies the intrinsic reactivity of human astrocytes in response to targeting GPCRs and delivers a bioengineered approach for organoid-based disease modeling and preclinical drug testing.
Topics: Adenosine Triphosphate; Astrocytes; Bioengineering; Calcium; Cell Line; GTP-Binding Protein alpha Subunits, Gq-G11; Glial Fibrillary Acidic Protein; Humans; Inflammation; Neural Stem Cells; Neurons; Organoids; Pluripotent Stem Cells; Receptors, G-Protein-Coupled; Reproducibility of Results; Spheroids, Cellular; Synaptophysin
PubMed: 35139144
DOI: 10.1083/jcb.202107135 -
Translational Neurodegeneration Oct 2022Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disease that affects neurons in the central nervous system and the spinal cord. As in...
BACKGROUND
Amyotrophic lateral sclerosis (ALS) is a devastating progressive neurodegenerative disease that affects neurons in the central nervous system and the spinal cord. As in many other neurodegenerative disorders, the genetic risk factors and pathogenesis of ALS involve dysregulation of cytoskeleton and neuronal transport. Notably, sensory and motor neuron diseases such as hereditary sensory and autonomic neuropathy type 2 (HSAN2) and spastic paraplegia 30 (SPG30) share several causative genes with ALS, as well as having common clinical phenotypes. KIF1A encodes a kinesin 3 motor that transports presynaptic vesicle precursors (SVPs) and dense core vesicles and has been reported as a causative gene for HSAN2 and SPG30.
METHODS
Here, we analyzed whole-exome sequencing data from 941 patients with ALS to investigate the genetic association of KIF1A with ALS.
RESULTS
We identified rare damage variants (RDVs) in the KIF1A gene associated with ALS and delineated the clinical characteristics of ALS patients with KIF1A RDVs. Clinically, these patients tended to exhibit sensory disturbance. Interestingly, the majority of these variants are located at the C-terminal cargo-binding region of the KIF1A protein. Functional examination revealed that the ALS-associated KIF1A variants located in the C-terminal region preferentially enhanced the binding of SVPs containing RAB3A, VAMP2, and synaptophysin. Expression of several disease-related KIF1A mutants in cultured mouse cortical neurons led to enhanced colocalization of RAB3A or VAMP2 with the KIF1A motor.
CONCLUSIONS
Our study highlighted the importance of KIF1A motor-mediated transport in the pathogenesis of ALS, indicating KIF1A as an important player in the oligogenic scenario of ALS.
Topics: Animals; Mice; Amyotrophic Lateral Sclerosis; Hereditary Sensory and Autonomic Neuropathies; Kinesins; Neurodegenerative Diseases; Spastic Paraplegia, Hereditary; Synaptophysin; Vesicle-Associated Membrane Protein 2; Humans; Cells, Cultured
PubMed: 36284339
DOI: 10.1186/s40035-022-00320-2