-
Toxicology Letters May 2023Redox homeostasis, mitochondrial functions, and mitochondria-endoplasmic reticulum (ER) communication were evaluated in the striatum of rats after 3-nitropropionic acid...
Mitochondrial dysfunction, oxidative stress, ER stress and mitochondria-ER crosstalk alterations in a chemical rat model of Huntington's disease: Potential benefits of bezafibrate.
Redox homeostasis, mitochondrial functions, and mitochondria-endoplasmic reticulum (ER) communication were evaluated in the striatum of rats after 3-nitropropionic acid (3-NP) administration, a recognized chemical model of Huntington's disease (HD). 3-NP impaired redox homeostasis by increasing malondialdehyde levels at 28 days, decreasing glutathione (GSH) concentrations at 21 and 28 days, and the activities of glutathione peroxidase (GPx), superoxide dismutase (SOD) and glutathione S-transferase at 7, 21, and 28 days, catalase at 21 days, and glutathione reductase at 21 and 28 days. Impairment of mitochondrial respiration at 7 and 28 days after 3-NP administration was also observed, as well as reduced activities of succinate dehydrogenase (SDH) and respiratory chain complexes. 3-NP also impaired mitochondrial dynamics and the interactions between ER and mitochondria and induced ER-stress by increasing the levels of mitofusin-1, and of DRP1, VDAC1, Grp75 and Grp78. Synaptophysin levels were augmented at 7 days but reduced at 28 days after 3-NP injection. Finally, bezafibrate prevented 3-NP-induced alterations of the activities of SOD, GPx, SDH and respiratory chain complexes, DCFH oxidation and on the levels of GSH, VDAC1 and synaptophysin. Mitochondrial dysfunction and synaptic disruption may contribute to the pathophysiology of HD and bezafibrate may be considered as an adjuvant therapy for this disorder.
Topics: Rats; Animals; Huntington Disease; Rats, Wistar; Bezafibrate; Synaptophysin; Models, Chemical; Oxidative Stress; Glutathione; Superoxide Dismutase; Mitochondria; Propionates; Nitro Compounds
PubMed: 37116597
DOI: 10.1016/j.toxlet.2023.04.011 -
Molecular and Clinical Oncology Aug 2021Neuroendocrine tumors (NETs) comprise a heterogenous group of rare malignancies, which are increasing in incidence worldwide. To further understand the epidemiology of...
Neuroendocrine tumors (NETs) comprise a heterogenous group of rare malignancies, which are increasing in incidence worldwide. To further understand the epidemiology of NETs in the Republic of Panama, the present study used two study groups, which included patients from several hospitals and clinics throughout the country, who were referred to the three largest national reference centers: The Complejo Hospitalario Metropolitano, Hospital Santo Tomas and Instituto Oncologico Nacional. These two groups comprised a retrospective cohort, which included cases reported between 2016 and 2017, and a second cohort, which was retrospective, but data were continuously collected from patients diagnosed with NETs between 2018 and 2019. Data from 157 patients with NETs reported that 83% of patients were in the 40-80 years old age group. The majority of cases (46%) presented as grade G1 tumors, while 29% were G3. Computerized tomography scans with contrast, and analysis of the Ki-67 biomarker and immunohistology markers (chromogranin A and synaptophysin) was performed in the majority of the cases. The results revealed that the most frequent anatomical sites for the primary tumor were the colorectum (17.2%), pancreas (12.7%) and stomach (12.1%), and the most frequent organ with metastasis was the liver, accounting for 34% of all cases. In conclusion, the present study is the first comprehensive study of NET in Panama to the best of our knowledge, which provides evidence of the demographic characteristics of the population, clinical features and overall survival for the affected population in this Central American country.
PubMed: 34178328
DOI: 10.3892/mco.2021.2319 -
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 -
The Journal of Neuroscience : the... Apr 2021Synaptophysin (syp) is a major integral membrane protein of secretory vesicles. Previous work has demonstrated functions for syp in synaptic vesicle cycling,...
Synaptophysin (syp) is a major integral membrane protein of secretory vesicles. Previous work has demonstrated functions for syp in synaptic vesicle cycling, endocytosis, and synaptic plasticity, but the role of syp in the process of membrane fusion during Ca-triggered exocytosis remains poorly understood. Furthermore, although syp resides on both large dense-core and small synaptic vesicles, its role in dense-core vesicle function has received less attention compared with synaptic vesicle function. To explore the role of syp in membrane fusion and dense-core vesicle function, we used amperometry to measure catecholamine release from single vesicles in male and female mouse chromaffin cells with altered levels of syp and the related tetraspanner protein synaptogyrin (syg). Knocking out syp slightly reduced the frequency of vesicle fusion events below wild-type (WT) levels, but knocking out both syp and syg reduced the frequency 2-fold. Knocking out both proteins stabilized initial fusion pores, promoted fusion pore closure (kiss-and-run), and reduced late-stage fusion pore expansion. Introduction of a syp construct lacking its C-terminal dynamin-binding domain in syp knock-outs (KOs) increased the duration and fraction of kiss-and-run events, increased total catecholamine release per event, and reduced late-stage fusion pore expansion. These results demonstrated that syp and syg regulate dense-core vesicle function at multiple stages to initiate fusion, control the choice of mode between full-fusion and kiss-and-run, and influence the dynamics of both initial and late-stage fusion pores. The transmembrane domain (TMD) influences small initial fusion pores, and the C-terminal domain influences large late-stage fusion pores, possibly through an interaction with dynamin. The secretory vesicle protein synaptophysin (syp) is known to function in synaptic vesicle cycling, but its roles in dense-core vesicle functions, and in controlling membrane fusion during Ca-triggered exocytosis remain unclear. The present study used amperometry recording of catecholamine release from endocrine cells to assess the impact of syp and related proteins on membrane fusion. A detailed analysis of amperometric spikes arising from the exocytosis of single vesicles showed that these proteins influence fusion pores at multiple stages and control the choice between kiss-and-run and full-fusion. Experiments with a syp construct lacking its C terminus indicated that the transmembrane domain (TMD) influences the initial fusion pore, while the C-terminal domain influences later stages after fusion pore expansion.
Topics: Animals; Animals, Newborn; Catecholamines; Chromaffin Cells; Dynamins; Electrophysiological Phenomena; Exocytosis; Female; Membrane Fusion; Mice; Mice, Knockout; Pregnancy; Primary Cell Culture; Synaptic Vesicles; Synaptogyrins; Synaptophysin
PubMed: 33664131
DOI: 10.1523/JNEUROSCI.2833-20.2021 -
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 -
Life Sciences Jan 2021Methamphetamine (METH) has become a major public health problem because of its abuse and profound neurotoxic effects, causing alterations in brain structure and...
AIMS
Methamphetamine (METH) has become a major public health problem because of its abuse and profound neurotoxic effects, causing alterations in brain structure and function, and impairing cognitive functions, including attention, decision making, emotional memory, and working memory. This study aimed to determine whether melatonin (MEL), the circadian-control hormone, which has roles beyond circadian rhythm regulation, could restore METH-induced cognitive and neuronal impairment.
MAIN METHODS
Mice were treated with either METH (1 mg/kg) or saline for 7 days, followed by MEL (10 mg/kg) or saline for another 14 days. The Morris water maze (MWM) test was performed one day after the last saline or MEL injection. The hippocampal neuronal density, synaptic density, and receptors involved in learning and memory, along with downstream signaling molecules (NMDA receptor subunits GluN2A, GluN2B, and CaMKII) were investigated by immunoblotting.
KEY FINDINGS
METH administration significantly extended escape latency in learning phase and reduced the number of target crossings in memory test-phase as well as decreased the expression of BDNF, NMDA receptors, TrkB receptors, CaMKII, βIII tubulin, and synaptophysin. MEL treatment significantly ameliorated METH-induced increased escape latency, decreased the number of target crossings and decreased expression of BDNF, NMDA receptors, TrkB receptors, CaMKII, βIII tubulin and synaptophysin.
SIGNIFICANCE
METH administration impairs learning and memory in mice, and MEL administration restores METH-induced neuronal impairments which is probably through the changes in BDNF, NMDA receptors, TrkB receptors, CaMKII, βIII tubulin and synaptophysin. Therefore, MEL is potentially an innovative and promising treatment for learning and memory impairment of humans.
Topics: Animals; Central Nervous System Stimulants; Cognition; Hippocampus; Male; Maze Learning; Melatonin; Memory; Memory Disorders; Methamphetamine; Mice; Mice, Inbred ICR; Neurons
PubMed: 33278389
DOI: 10.1016/j.lfs.2020.118844 -
Journal of Chemical Neuroanatomy Jan 2020The arcuate and the paraventricular and lateral hypothalamic nuclei, related to hunger and satiety control, are generally compromised by excess fatty acids. In this...
The arcuate and the paraventricular and lateral hypothalamic nuclei, related to hunger and satiety control, are generally compromised by excess fatty acids. In this situation, fatty acids cause inflammation via TLR4 (toll like receptor 4) and the nuclei become less responsive to the hormones leptin and insulin, contributing to the development of obesity. In this work, these nuclei were analyzed in animals fed with high-fat diet and submitted to swimming without and with load for two months. For this, frontal sections of the hypothalamus were immunolabelled with GFAP (glial fibrillary acidic protein), synaptophysin, IL-6 (interleukin 6) and TLR4. Also, proteins extracted from the hypothalamus were analyzed using Western blotting (GFAP and synaptophysin), fluorometric analysis for caspases 3 and 7, and CBA (cytometric bead array) for Th1, Th2, and Th17 profiles. The high-fat diet significantly caused overweight and, in the hypothalamus, decreased synapses and increased astrocytic reactivity. The swimming with load, especially 80 % of the maximum load, reduced those consequences. The high-fat diet increased TLR4 in the arcuate nucleus and the swimming exercise with 80 % of the maximum load showed a tendency of reducing this expression. Swimming did not significantly influence the inflammatory or anti-inflammatory cytokines in the hypothalamus or in plasma. The high-fat diet in sedentary animals increased the expression of caspases 3 and 7 and swimming practice reduced this increment to levels compatible with animals fed on a normal diet. The set of results conclude that the impact of swimming on the damage caused in the hypothalamus by a high-fat diet is positive. The different aspects analyzed in here point to better cellular viability and conservation of the synapses in the hypothalamic nuclei of overweight animals that practiced swimming with a load.
Topics: Animals; Caspases; Diet, High-Fat; Glial Fibrillary Acidic Protein; Hypothalamus; Interleukin-6; Male; Mice; Neurons; Overweight; Swimming; Synaptophysin; Toll-Like Receptor 4
PubMed: 31726089
DOI: 10.1016/j.jchemneu.2019.101713 -
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 -
Diagnostics (Basel, Switzerland) Nov 2021Insulinoma-associated protein 1 (INSM1) has been considered as a novel immunostain for neuroendocrine tumors (NETs) and is hypothesized to be more reliable than... (Review)
Review
Insulinoma-associated protein 1 (INSM1) has been considered as a novel immunostain for neuroendocrine tumors (NETs) and is hypothesized to be more reliable than first-generation NET biomarkers, such as CGA (chromogranin A), SYP (synaptophysin) and CD56 (neural cell adhesion molecule). In this review, we summarize existing literature on INSM1's reliability as an immunostain for detection of various NETs, its results in comparison to first-generation NET biomarkers, and its expression in both non-NETs and benign tissues/cells on cytology specimens (cell blocks/smears).
PubMed: 34943408
DOI: 10.3390/diagnostics11122172