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Multiple Sclerosis (Houndmills,... Apr 2021Synaptic loss is a feature of multiple sclerosis pathology that can be seen even in normal-appearing gray matter. Opsonization of synapses with complement components may...
BACKGROUND
Synaptic loss is a feature of multiple sclerosis pathology that can be seen even in normal-appearing gray matter. Opsonization of synapses with complement components may underlie pathologic synapse loss.
OBJECTIVE
We sought to determine whether circulating neuronal-enriched and astrocytic-enriched extracellular vesicles (NEVs and AEVs) provide biomarkers reflecting complement-mediated synaptic loss in multiple sclerosis.
METHODS
From plasma of 61 people with multiple sclerosis (46 relapsing-remitting multiple sclerosis (RRMS) and 15 progressive MS) and 31 healthy controls, we immunocaptured L1CAM + NEVs and GLAST + AEVs. We measured pre- and post-synaptic proteins synaptopodin and synaptophysin in NEVs and complement components (C1q, C3, C3b/iC3b, C4, C5, C5a, C9, Factor B, and Factor H) in AEVs, total circulating EVs, and neat plasma.
RESULTS
We found lower levels of NEV synaptopodin and synaptophysin in MS compared to controls ( < 0.0001 for both). In AEVs, we found higher levels of multiple complement cascade components in people with MS compared to controls; these differences were not noted in total EVs or neat plasma. Strikingly, there were strong inverse correlations between NEV synaptic proteins and multiple AEV complement components in MS, but not in controls.
CONCLUSION
Circulating EVs could identify synaptic loss in MS and suggest a link between astrocytic complement production and synaptic loss.
Topics: Biomarkers; Complement Activation; Complement System Proteins; Extracellular Vesicles; Humans; Multiple Sclerosis
PubMed: 32669030
DOI: 10.1177/1352458520924590 -
Fukutin regulates tau phosphorylation and synaptic function: Novel properties of fukutin in neurons.Neuropathology : Official Journal of... Feb 2022Fukutin, a product of the causative gene of Fukuyama congenital muscular dystrophy (FCMD), is known to be responsible for basement membrane formation. Patients with FCMD...
Fukutin, a product of the causative gene of Fukuyama congenital muscular dystrophy (FCMD), is known to be responsible for basement membrane formation. Patients with FCMD exhibit not only muscular dystrophy but also central nervous system abnormalities, including polymicrogyria and neurofibrillary tangles (NFTs) in the cerebral cortex. The formation of NFTs cannot be explained by basement membrane disorganization. To determine the involvement of fukutin in the NFT formation, we performed molecular pathological investigations using autopsied human brains and cultured neurons of a cell line (SH-SY5Y). In human brains, NFTs, identified with an antibody against phosphorylated tau (p-tau), were observed in FCMD patients but not age-matched control subjects and were localized in cortical neurons lacking somatic immunoreactivity for glutamic acid decarboxylase (GAD), a marker of inhibitory neurons. In FCMD brains, NFTs were mainly distributed in lesions of polymicrogyria. Immunofluorescence staining revealed the colocalization of immunoreactivities for p-tau and phosphorylated glycogen synthase kinase-3β (GSK-3β), a potential tau kinase, in the somatic cytoplasm of SH-SY5Y cells; both the immunoreactivities were increased by fukutin knockdown and reduced by fukutin overexpression. Western blot analysis using SH-SY5Y cells revealed consistent results. Enzyme-linked immunosorbent assay (ELISA) confirmed the binding affinity of fukutin to tau and GSK-3β in SH-SY5Y cells. In the human brains, the density of GAD-immunoreactive neurons in the frontal cortex was significantly higher in the FCMD group than in the control group. GAD immunoreactivity on Western blots of SH-SY5Y cells was significantly increased by fukutin knockdown. On immunofluorescence staining, immunoreactivities for fukutin and GAD were colocalized in the somatic cytoplasm of the human brains and SH-SY5Y cells, whereas those for fukutin and synaptophysin were colocalized in the neuropil of the human brains and the cytoplasm of SH-SY5Y cells. ELISA confirmed the binding affinity of fukutin to GAD and synaptophysin in SH-SY5Y cells. The present results provide in vivo and in vitro evidence for novel properties of fukutin as follows: (i) there is an inverse relationship between fukutin expression and GSK-3β/tau phosphorylation in neurons; (ii) fukutin binds to GSK-3β and tau; (iii) tau phosphorylation occurs in non-GAD-immunoreactive neurons in FCMD brains; (iv) neuronal GAD expression is upregulated in the absence of fukutin; and (v) fukutin binds to GAD and synaptophysin in presynaptic vesicles of neurons.
Topics: Brain; Glycogen Synthase Kinase 3 beta; Humans; Neurofibrillary Tangles; Neurons; Phosphorylation; tau Proteins
PubMed: 35026860
DOI: 10.1111/neup.12797 -
Journal of Cancer Research and... 2021The objective of the evaluate was to study and determine the usefulness of immunohistochemistry (IHC) staining in neoplastic lung lesions.
OBJECTIVES
The objective of the evaluate was to study and determine the usefulness of immunohistochemistry (IHC) staining in neoplastic lung lesions.
MATERIALS AND METHODS
We evaluated seven IHC stains in fifty lung cancers that included adenocarcinoma (AC), squamous cell carcinoma (SCC), small cell carcinoma, and carcinoid tumors.
RESULTS
P63 was expressed in all the cases of SCCs and thyroid transcription factor-1 (TTF-1) was expressed in all cases of ACs. CK 5/6 was expressed in 77.77% of SCCs and CK 7 was expressed in 92.59% of ACs. Synaptophysin and chromogranin-A were expressed in 100% of neuroendocrine (NE) carcinomas.
CONCLUSION
P63 and TTF-1 are sensitive markers for SCCs and ACs. Synaptophysin and Chromogranin-A are sensitive markers for NE carcinomas.
Topics: Adenocarcinoma of Lung; Biomarkers, Tumor; Carcinoma, Non-Small-Cell Lung; Carcinoma, Squamous Cell; Diagnosis, Differential; Humans; Immunohistochemistry; Lung Neoplasms; Prognosis; Small Cell Lung Carcinoma
PubMed: 34916368
DOI: 10.4103/jcrt.JCRT_187_19 -
Journal of Clinical Medicine Sep 2023According to the 2019 World Health Organization (WHO) classification of gastric neuroendocrine neoplasms, gastric neuroendocrine carcinoma (GNEC) can be further divided...
BACKGROUND
According to the 2019 World Health Organization (WHO) classification of gastric neuroendocrine neoplasms, gastric neuroendocrine carcinoma (GNEC) can be further divided into gastric large-cell neuroendocrine carcinoma (GLNEC) and gastric small-cell neuroendocrine carcinoma (GSNEC). Whether the prognoses of the two types have a discrepancy has long been disputed.
METHOD
We collected patients diagnosed with GLNEC or GSNEC in the National Cancer Center of China between January 2000 and December 2020. The characteristics and survival outcomes were compared between the two groups. We further verified our conclusion using the SEER dataset.
RESULTS
A total of 114 GNEC patients, including 82 patients with GLNEC and 32 patients with GSNEC, have completed treatment in our hospital. Clinicopathologic differences were not observed between patients with GSNEC and GLNEC concerning the sex, age, body mass index, Charlson Comorbidity Index, tumor location, tumor size, stage, treatment received, the expression of neuroendocrine markers (CD56, Chromogranin A, synaptophysin), and score on the Ki-67 index. The 1-year, 3-year, and 5-year overall survival rates of GLNEC and GSNEC were 89.0%, 60.5%, and 52.4%, and 93.8%, 56.3%, and 52.7%, which showed no statistically significant differences. This result was confirmed further by using the SEER dataset after the inverse probability of treatment weighting.
CONCLUSIONS
Although with different cell morphology, the comparison of prognosis between the GLNEC and GSNEC has no significant statistical difference.
PubMed: 37762979
DOI: 10.3390/jcm12186039 -
Case Reports in Gastroenterology 2021Gastric mixed adenocarcinoma-neuroendocrine tumor (NET) is a rare composite tumor, and a limited number of studies have reported on it. A 77-year-old man was admitted to...
Gastric mixed adenocarcinoma-neuroendocrine tumor (NET) is a rare composite tumor, and a limited number of studies have reported on it. A 77-year-old man was admitted to our hospital because of acute cholecystitis. He underwent a cholecystectomy. Esophagogastroduodenoscopy during his admission revealed a slightly elevated tumor, and biopsy demonstrated a well-differentiated tubular adenocarcinoma. The tumor was resected completely by endoscopic submucosal dissection. Histological findings showed that it measured 9 mm in diameter, was located within the mucosa, and consisted of well-differentiated tubular adenocarcinoma and a NET G1. The NET was covered with adenocarcinoma and both components exhibited histological continuity. The NET and a part of the adenocarcinoma component showed a positive reaction for chromogranin A and synaptophysin. Neither enterochromaffin-like cell hyperplasia nor endocrine cell micronest surrounded the tumor. The diagnosis was gastric mixed adenocarcinoma-NET. The histological continuity between the two components can be likened to the same histogenesis.
PubMed: 33790721
DOI: 10.1159/000513802 -
IScience Sep 2023Prolonged withdrawal from opioids leads to negative emotions. Kappa opioid receptor (KOR) plays an important role in opioid addiction and affective disorders. However,...
Prolonged withdrawal from opioids leads to negative emotions. Kappa opioid receptor (KOR) plays an important role in opioid addiction and affective disorders. However, the underlying mechanism of KOR in withdrawal-related depression is still lacking. We found that escitalopram treatment had a limited effect in improving depression symptoms in heroin-dependent patients. In mice, we demonstrated prolonged (4 weeks) but not acute (24 h) withdrawal from morphine induced depressive-like behaviors. The number of c-Fos positive cells and the expression of KOR in the nucleus accumbens (NAc), were significantly increased in the prolonged morphine withdrawal mice. Conditional KOR knockdown in NAc significantly improved depressive-like behaviors. Repeated but not acute treatment with the KOR antagonist norBNI improved depressive-like behaviors and reversed PSD95, synaptophysin, -ERK, -CREB, and BDNF in NAc. This study demonstrated the important role of striatal KOR in morphine withdrawal-related depressive-like behaviors and offered therapeutic potential for the treatment of withdrawal-related depression.
PubMed: 37636073
DOI: 10.1016/j.isci.2023.107536 -
Ecotoxicology and Environmental Safety Nov 2022Ozone pollution has been associated with several adverse effects, including memory impairment, intellectual retardation, emotional disturbances. However, the potential...
Ozone pollution has been associated with several adverse effects, including memory impairment, intellectual retardation, emotional disturbances. However, the potential mechanisms remain uncertain. The present study aimed to investigate whether ozone (O) regulates synaptic plasticity through PI3K/Akt/GSK3β signaling pathway and induces neurobehavioral modifications among the young rats. In vivo, the newborn rats were used to construct the animal model of early postnatal O treatment. In vitro, this study measured the effect of different concentrations of serum from O treated rats on the viability of the PC12 cells, and investigated the modifications of synaptic plasticity and PI3K/Akt/GSK3β signaling pathway in the hippocampus and PC12 cells after O treated. The results revealed significant depression-like behavior and increased hippocampal histopathological damage in the young rats after O treated. Compared with the control group, the expression levels of synaptic related proteins including Drebrin, PSD95, Synaptophysin and PIK3R1, p-Akt, and p-GSK3β were decreased in the O treated group. In vitro assays, a significant reduction in Drebrin, PSD95, Synaptophysin, PIK3R1, p-Akt, and p-GSK3β was found in PC12 cells after O serum treated. While 740Y-P (a specific PI3K activator) administered, the expression levels of Drebrin, PSD95, Synaptophysin, PIK3R1, p-Akt, and p-GSK3β in the 740Y-P + O group were significantly elevated in vivo and vitro compared with the O-only group. In addition, miRNAs modulating PIK3R1 were screened on bioinformatics website, the study found aberrant expression of miR-221-3p in the hippocampus and serum of O treated group. Inhibition of miR-221-3p expression effectively reversed the reduction of Drebrin, PSD95, Synaptophysin, PIK3R1, p-Akt, and p-GSK3β in PC12 cells induced by O treatment. Altogether, these studies indicate that O restrained the expression of PI3K/Akt/GSK3β signaling pathway and impaired synaptic plasticity that resulted in depressive-like behavior in young rats. Moreover, miR-221-3p plays an important role in this procedure by regulating PIK3R1.
Topics: Rats; Animals; Phosphatidylinositol 3-Kinases; Proto-Oncogene Proteins c-akt; Glycogen Synthase Kinase 3 beta; Synaptophysin; Ozone; Neuronal Plasticity; MicroRNAs
PubMed: 36228356
DOI: 10.1016/j.ecoenv.2022.114171 -
Ecancermedicalscience 2023Primary breast neuroendocrine neoplasms (BNENs) are a rare form of breast cancer, accounting for less than 0.1% of all breast malignancies. These neoplasms have a...
Primary breast neuroendocrine neoplasms (BNENs) are a rare form of breast cancer, accounting for less than 0.1% of all breast malignancies. These neoplasms have a similar clinical presentation as conventional breast carcinomas, differing mainly in their histopathology and expression of neuroendocrine (NE) markers, chromogranin and synaptophysin. Owing to their rarity, current knowledge of these tumours comes mainly from corroborative case reports or retrospective case series. There is hence a lack of randomised data on the treatment of these entities and current protocol suggests similar treatment as that of conventional breast carcinomas. We report the case of a 48-year-old with a breast mass, which on further work-up was diagnosed as locally advanced carcinoma breast, that required a mastectomy and axillary node dissection on the same side and revealed NE differentiation on histopathological examination. Hence, immunohistochemical staining was indicated which confirmed NE differentiation. We discuss the current knowledge on incidence, demographics, diagnosis, histopathological and staining characteristics, prognostic factors and treatment modalities of BNENs.
PubMed: 37113730
DOI: 10.3332/ecancer.2023.1520 -
Archives of Pathology & Laboratory... Sep 2020The diagnostic distinction of pulmonary neuroendocrine (NE) tumors from non-small cell lung carcinomas (NSCLCs) is clinically relevant for prognostication and treatment.... (Review)
Review
CONTEXT.—
The diagnostic distinction of pulmonary neuroendocrine (NE) tumors from non-small cell lung carcinomas (NSCLCs) is clinically relevant for prognostication and treatment. Diagnosis is based on morphology and immunohistochemical staining.
OBJECTIVE.—
To determine the diagnostic value of insulinoma-associated protein 1 (INSM1), in comparison with established NE markers, in pulmonary tumors.
DESIGN.—
Fifty-four pulmonary NE tumors and 632 NSCLCs were stained for INSM1, CD56, chromogranin A, and synaptophysin. In a subset, gene expression data were available for analysis. Also, 419 metastases to the lungs were stained for INSM1. A literature search identified 39 additional studies with data on NE markers in lung cancers from the last 15 years. Seven of these included data on INSM1.
RESULTS.—
A positive INSM1 staining was seen in 39 of 54 NE tumors (72%) and 6 of 623 NSCLCs (1%). The corresponding numbers were 47 of 54 (87%) and 14 of 626 (2%) for CD56, 30 of 54 (56%) and 6 of 629 (1%) for chromogranin A, and 46 of 54 (85%) and 49 of 630 (8%) for synaptophysin, respectively. Analysis of literature data revealed that CD56 and INSM1 were the best markers for identification of high-grade NE pulmonary tumors when considering both sensitivity and specificity, while synaptophysin also showed good sensitivity. INSM1 gene expression was clearly associated with NE histology.
CONCLUSIONS.—
The solid data of both our and previous studies confirm the diagnostic value of INSM1 as a NE marker in pulmonary pathology. The combination of CD56 with INSM1 and/or synaptophysin should be the first-hand choice to confirm pulmonary high-grade NE tumors. INSM1 gene expression could be used to predict NE tumor histology.
Topics: Adenocarcinoma of Lung; Biomarkers, Tumor; CD56 Antigen; Carcinoma, Squamous Cell; Chromogranin A; Humans; Immunohistochemistry; Lung Neoplasms; Repressor Proteins; Synaptophysin
PubMed: 31913660
DOI: 10.5858/arpa.2019-0250-OA -
Frontiers in Synaptic Neuroscience 2021Synaptic vesicle release is regulated by upwards of 30 proteins at the fusion complex alone, but disruptions in any one of these components can have devastating...
Synaptic vesicle release is regulated by upwards of 30 proteins at the fusion complex alone, but disruptions in any one of these components can have devastating consequences for neuronal communication. Aberrant molecular responses to calcium signaling at the pre-synaptic terminal dramatically affect vesicle trafficking, docking, fusion, and release. At the organismal level, this is reflected in disorders such as epilepsy, depression, and neurodegeneration. Among the myriad pre-synaptic proteins, perhaps the most functionally mysterious is synaptophysin (SYP). On its own, this vesicular transmembrane protein has been proposed to function as a calcium sensor, a cholesterol-binding protein, and to form ion channels across the phospholipid bilayer. The downstream effects of these functions are largely unknown. The physiological relevance of SYP is readily apparent in its interaction with synaptobrevin (VAMP2), an integral element of the neuronal SNARE complex. SNAREs, soluble NSF attachment protein receptors, comprise a family of proteins essential for vesicle fusion. The complex formed by SYP and VAMP2 is thought to be involved in both trafficking to the pre-synaptic membrane as well as regulation of SNARE complex formation. Recent structural observations specifically implicate the SYP/VAMP2 complex in anchoring the SNARE assembly at the pre-synaptic membrane prior to vesicle fusion. Thus, the SYP/VAMP2 complex appears vital to the form and function of neuronal exocytotic machinery.
PubMed: 34616284
DOI: 10.3389/fnsyn.2021.740318