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• Acute social defeat alters morphology of microglia in infralimbic cortex. • Dominant hamsters show less reactive microglia and cell damage than subordinates. • Blocking microglia activity with minocycline increased stress-related behavior. • Microglia activity in the infralimbic cortex may be necessary for stress coping. Chronic stress increases activity of the brain's innate immune system and impairs function of the medial prefrontal cortex (mPFC). However, whether acute stress triggers similar neuroimmune mechanisms is poorly understood. Across four studies, we used a Syrian hamster model to investigate whether acute stress drives changes in mPFC microglia in a time-, subregion-, and social status-dependent manner. We found that acute social defeat increased expression of ionized calcium binding adapter molecule 1 (Iba1) in the infralimbic (IL) and prelimbic (PL) and altered the morphology Iba1+ cells 1, 2, and 7 days after social defeat. We also investigated whether acute defeat induced tissue degeneration and reductions of synaptic plasticity 2 days post-defeat. We found that while social defeat increased deposition of cellular debris and reduced synaptophysin immunoreactivity in the PL and IL, treatment with minocycline protected against these cellular changes. Finally, we tested whether a reduced conditioned defeat response in dominant compared to subordinate hamsters was associated with changes in microglia reactivity in the IL and PL. We found that while subordinate hamsters and those without an established dominance relationships showed defeat-induced changes in morphology of Iba1+ cells and cellular degeneration, dominant hamsters showed resistance to these effects of social defeat. Taken together, these findings indicate that acute social defeat alters microglial morphology, increases markers of tissue degradation, and impairs structural integrity in the IL and PL, and that experience winning competitive interactions can specifically protect the IL and reduce stress vulnerability. [ABSTRACT FROM AUTHOR]

AbstractPurposeMethodsResultsConclusionBackground: Noise-induced cochlear synaptopathy has recently emerged as a focus in hearing research.This study aimed to examine the impact of repeated noise exposure on the quantification and mRNA expression levels of cochlear synapses.Measurements were conducted at baseline, 1 day, and 14 days post-exposure to 88 or 97 dB SPL noise (2 h/day for 7 days, frequency range 2-20 kHz). Auditory brainstem responses (ABRs), immunofluorescence and quantitative real-time PCR (qRT-PCR) were used to examine the results.1. Exposure to 88 dB SPL caused minimal changes in ABRs, ribbon morphology and medial olivocochlear (MOC) efferent synapses; elevation of synaptophysin(SYP) and α9α10 nAchR mRNA levels were observed. 2. Exposure to 97 dB SPL caused threshold shift and synaptopathy of ribbon and MOC; downregulation of α10nAchR, SYP and ctbp2 mRNA levels were observed.Noise-induced cochlear synaptic degeneration involves both afferent and efferent synaptopathy. [ABSTRACT FROM AUTHOR]

This article discusses the misdiagnosis of synaptophysin-expressing gastric glomus tumors as gastric neuroendocrine tumors. The authors present two cases of patients with gastric glomus tumors that were initially misdiagnosed due to the expression of synaptophysin. The article emphasizes the importance of using a comprehensive panel of immunomarkers, including chromogranin, CD56, and keratin, to differentiate between neuroendocrine tumors and glomus tumors. The authors also highlight the potential diagnostic pitfalls and implications of synaptophysin expression in visceral glomus tumors. [Extracted from the article]

Alzheimer's disease (AD) is a progressive neurodegenerative disorder pathologically characterized by the deposition of amyloid beta (Ab) plaques and neurofibrillary tangles (NFTs) in the brain. The accumulation of these aggregated proteins causes memory and synaptic dysfunction, neuroinflammation, and oxidative stress. This research study is significant as it aims to assess the neuroprotective properties of vitamin E (VE) analog Trolox in an Ab1-42-induced AD mouse model. Ab1-42 5µL/5min/mouse was injected intracerebroventricularly (i.c.v.) into wild-type adult mice brain to induce AD-like neurotoxicity. For biochemical analysis, Western blotting and confocal microscopy were performed. Remarkably, intraperitoneal (i.p.) treatment of Trolox (30 mg/kg/mouse for 2 weeks) reduced the AD pathology by reducing the expression of Ab, phosphorylated tau (p-tau), and b-site amyloid precursor protein cleaving enzyme1 (BACE1) in both cortex and hippocampus regions of mice brain. Furthermore, Trolox-treatment decreased neuroinflammation by inhibiting Toll-like receptor 4 (TLR4), phosphorylated nuclear factor-kB (pNF-kB) and interleukin-1b (IL-1b), and other inflammatory biomarkers of glial cells [ionized calcium-binding adaptor molecule 1 (Iba1) and glial fibrillary acidic protein (GFAP)]. Moreover, Trolox reduced oxidative stress by enhancing the expression of nuclear factor erythroid-related factor 2 (NRF2) and heme oxygenase 1 (HO1). Similarly, Trolox-induced synaptic markers, including synaptosomal associated protein 23 (SNAP23), synaptophysin (SYN), and post-synaptic density protein 95 (PSD-95), and memory functions in AD mice. Our findings could provide a useful and novel strategy for investigating new medications to treat AD-associated neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

• Understanding MDD and its pathophysiology aids in treatment improvement. • Synaptic plasticity is crucial in MDD and drug response, involving key proteins. • Stress impacts glutamatergic neurons in MDD, but antidepressants can help. • Ketamine and non-drug methods may treat MDD by enhancing spinogenesis. Major depressive disorder (MDD) has demonstrated its negative impact on various aspects of the lives of those affected. Although several therapies have been developed over the years, it remains a challenge for mental health professionals. Thus, understanding the pathophysiology of MDD is necessary to improve existing treatment options or seek new therapeutic alternatives. Clinical and preclinical studies in animal models of depression have shown the involvement of synaptic plasticity in both the development of MDD and the response to available drugs. However, synaptic plasticity involves a cascade of events, including the action of presynaptic proteins such as synaptophysin and synapsins and postsynaptic proteins such as postsynaptic density-95 (PSD-95). Additionally, several factors can negatively impact the process of spinogenesis/neurogenesis, which are related to many outcomes, including MDD. Thus, this narrative review aims to deepen the understanding of the involvement of synaptic formations and their components in the pathophysiology and treatment of MDD. [ABSTRACT FROM AUTHOR]

Background: Depression is a chronic psychiatric disease of multifactorial etiology, and its pathophysiology is not fully understood. Stress and other chronic inflammatory pathologies are shared risk factors for psychiatric diseases, and comorbidities are features of major depression. Epidemiological evidence suggests that periodontitis, as a source of low-grade chronic systemic inflammation, may be associated with depression, but the underlying mechanisms are not well understood. Methods: Periodontitis (P) was induced in Wistar: Han rats through oral gavage with the pathogenic bacteria Porphyromonas gingivalis and Fusobacterium nucleatum for 12 weeks, followed by 3 weeks of chronic mild stress (CMS) to induce depressive-like behavior. The following four groups were established (n = 12 rats/group): periodontitis and CMS (P + CMS+), periodontitis without CMS, CMS without periodontitis, and control. The morphology and inflammatory phenotype of microglia in the frontal cortex (FC) were studied using immunofluorescence and bioinformatics tools. The endocannabinoid (EC) signaling and proteins related to synaptic plasticity were analyzed in FC samples using biochemical and immunohistochemical techniques. Results: Ultrastructural and fractal analyses of FC revealed a significant increase in the complexity and heterogeneity of Iba1 + parenchymal microglia in the combined experimental model (P + CMS+) and increased expression of the proinflammatory marker inducible nitric oxide synthase (iNOS), while there were no changes in the expression of cannabinoid receptor 2 (CB2). In the FC protein extracts of the P + CMS + animals, there was a decrease in the levels of the EC metabolic enzymes N-acyl phosphatidylethanolamine-specific phospholipase D (NAPE-PLD), diacylglycerol lipase (DAGL), and monoacylglycerol lipase (MAGL) compared to those in the controls, which extended to protein expression in neurons and in FC extracts of cannabinoid receptor 1 (CB1) and to the intracellular signaling molecules phosphatidylinositol-3-kinase (PI3K), protein kinase B (Akt) and extracellular signal-regulated kinase 1/2 (ERK1/2). The protein levels of brain-derived neurotrophic factor (BDNF) and synaptophysin were also lower in P + CMS + animals than in controls. Conclusions: The combined effects on microglial morphology and inflammatory phenotype, the EC signaling, and proteins related to synaptic plasticity in P + CMS + animals may represent relevant mechanisms explaining the association between periodontitis and depression. These findings highlight potential therapeutic targets that warrant further investigation. [ABSTRACT FROM AUTHOR]

ATG9A is the only integral membrane protein among core autophagy-related (ATG) proteins. We previously found that ATG9A does not co-assemble into synaptophysin-positive vesicles, but rather, localizes to a distinct pool of vesicles within synapsin condensates in both fibroblasts and nerve terminals. The endocytic origin of these vesicles further suggests the existence of different intracellular sorting or segregation mechanisms for ATG9A and synaptophysin in cells. However, the precise underlying mechanism remains largely unknown. In this follow-up study, we investigated the endosomal localization of these two proteins by exploiting the advantages of a Rab5 mutant that induces the formation of enlarged endosomes. Notably, ATG9A and synaptophysin intermix perfectly and do not segregate on giant endosomes, indicating that the separation of these two proteins is not solely caused by the inherent properties of the proteins, but possibly by other unknown factors. [ABSTRACT FROM AUTHOR]

Mixed neuroendocrine and non-neuroendocrine neoplasms, recently recognized in the WHO classification as (MiNEN), are rare tumors of the gastrointestinal tract. These tumors are composed of two distinct cellular components; a well- or poorly differentiated neuroendocrine tumor and a non-neuroendocrine tumor, usually in the form of an adenocarcinoma, either admixed with or adjacent to one another. A rarer phenotype is a tumor in which the endocrine and epithelial cell features occur within the same cell; i.e. amphicrine carcinoma. Herein, we report the case of an 80-year-old female patient who presented with melena, and who, on biopsy was diagnosed as amphicrine carcinoma that was mismatch repair deficient (MMRd) with loss of MLH1/PMS2 nuclear expression by immunohistochemistry. The histological and immunohistochemical findings of this rare entity are presented with review of pertinent literature. [ABSTRACT FROM AUTHOR]

Background: Premature ejaculation (PE) is the most prevalent sexual dysfunction among men. Eejaculation involves a complex nervous mechanism in which the ejaculatory centers play a key role in modulating sperm emission. Although treatment possibilities span from psychotherapy to pharmacological approaches, results show inconsistent efficacy. In this context, the emergence of repetitive transcranial magnetic stimulation (rTMS) as a non‐invasive neuromodulatory approach represents a compelling avenue for potential therapeutic exploration. Objective: To investigate whether high‐frequency transcranial magnetic stimulation can modulate the ejaculatory behavior of rats with rapid ejaculation by altering neurotransmitter levels and neuroplasticity in the hippocampus. Methods: Rats have been screened for rapid ejaculation by observing behavioral indices of mating, and subsequently divided into two groups. The intervention group was administered with a 10 Hz rTMS stimulation, whereas the control group received a sham procedure. Upon the delivery of rTMS, we investigated ejaculation latency (EL), the hippocampal 5‐hydroxytryptamine (5‐HT) concentration, brain‐derived neurotrophic factor (BDNF), synaptophysin (SYN), and postsynaptic density protein 95 (PSD95) expressions, as well as BDNF‐receptor tyrosine kinase receptor B (TrkB) pathway upregulation. Results: After 14 days, EL was increased in the intervention group compared with the control group. 5‐HT concentration in the hippocampal region was increased, and high‐frequency rTMS activated the BDNF and TrkB pathways, including phosphorylation of cAMP response element‐binding protein (CREB), and upregulated the transcription and protein expression of SYN, and PSD95. Conclusion: RTMS upregulates BDNF, SYN, and PSD95 expression through activation of the BDNF–TrkB pathway and increases brain 5‐hydroxytryptamine thereby regulating neuroplasticity and improving ejaculation. [ABSTRACT FROM AUTHOR]

A high-fat diet can modify the composition of gut microbiota, resulting in dysbiosis. Changes in gut microbiota composition can lead to increased permeability of the gut barrier, allowing bacterial products like lipopolysaccharides (LPS) to enter circulation. This process can initiate systemic inflammation and contribute to neuroinflammation. Empagliflozin (EF), an SGLT2 inhibitor-type hypoglycemic drug, has been reported to treat neuroinflammation. However, there is a lack of evidence showing that EF regulates the gut microbiota axis to control neuroinflammation in HFD models. In this study, we explored whether EF could improve neuroinflammation caused by an HFD via regulation of the gut microbiota and the mechanism underlying this phenomenon. Our data revealed that EF alleviates pathological brain injury, reduces the reactive proliferation of astrocytes, and increases the expression of synaptophysin. In addition, the levels of inflammatory factors in hippocampal tissue were significantly decreased after EF intervention. Subsequently, the results of 16S rRNA gene sequencing showed that EF could change the microbial community structure of mice, indicating that the abundance of Lactococcus , Ligilactobacillus and other microbial populations decreased dramatically. Therefore, EF alleviates neuroinflammation by inhibiting gut microbiota-mediated astrocyte activation in the brains of high-fat diet-fed mice. Our study focused on the gut-brain axis, and broader research on neuroinflammation can provide a more holistic understanding of the mechanisms driving neurodegenerative diseases and inform the development of effective strategies to mitigate their impact on brain health. The results provide strong evidence supporting the larger clinical application of EF. Schematic illustration of EF alleviates neuroinflammation via integrating analysis of the microbiota-gut-brain axis in high-fat diet-induced mice. [Display omitted] • RNA-seq and 16S rRNA were used to detect genes and flora species in HFD mice after administration of EF. • EF alleviates neuroinflammation via improved gut microbiota profile and affects the Akt-mTOR pathway. • The role of EF in ameliorating neuroinflammation induced by a HFD via the gut-brain axis were to investigated. [ABSTRACT FROM AUTHOR]

Objective: Our purpose was to investigate the clinicopathological diagnostic value of immunohistochemical antibody for insulinoma-associated protein 1 (INSM1) in biopsy specimens of SCLC. Methods: Biopsy specimens of SCLC diagnosed at the pathology department of Tangshan Gongren Hospital from January 2022 to June 2023 were selected. INSM1 expression was detected and compared with conventional neuroendocrine markers synaptophysin (SYP), chromogranin A (CHGA), and CD56 regarding expression sensitivity and specificity. Results: The sensitivity of INSM1 expression was significantly higher than that of CHGA (95% vs 50%, P =.000), but there was no statistically significant difference in the specificity of INSM1, SYP, CHGA, and CD56 expression (100% vs 94% vs 98% vs 92%, respectively, P =.241, 1.000,.126). Conclusions: INSM1 antibody shows high sensitivity and specificity in the expression of SCLC and serves as a reliable immunohistochemical marker in the clinicopathological diagnosis of SCLC in biopsy specimens. [ABSTRACT FROM AUTHOR]

Selective serotonin reuptake inhibitors (SSRIs) are widely used drugs for the treatment of depression. Citalopram is one of the most prescribed SSRIs that is useful for the treatment of depression, obsessive–compulsive disorder, and anxiety disorders. On the other hand, crocin (active constitute of saffron) has pro-cognitive and mood enhancer effects. Also, both citalopram and crocin affect the function and expression of brain-derived neurotrophic factor (BDNF) and synaptophysin, two molecular factors that are involved in cognitive functions and mood. In the present study, we aim to investigate the interaction effect of citalopram and crocin on rats' performance in the open field test (locomotor activity and anxiety-like behavior) and the shuttle box (passive avoidance memory). Citalopram was injected at the doses of 10, 30, and 50 mg/kg, and crocin was injected at the dose of 50 mg/kg; all administrations were intraperitoneal. Real-time PCR was used to assess the expression level of BDNF and synaptophysin in the hippocampus. The results showed that citalopram (30 and 50 mg/kg) impaired passive avoidance memory and decreased BDNF and synaptophysin expression in the hippocampus, while crocin reversed memory impairment, and BDNF and synaptophysin expression in the hippocampus of rats received citalopram 30 mg/kg. Also, crocin partially showed these effects in rats that received citalopram 50 mg/kg. The results of the open field test were unchanged. In conclusion, we suggested that BDNF and synaptophysin may be involved in the effects of both citalopram and crocin. [ABSTRACT FROM AUTHOR]

Abstract ATG9A is the only integral membrane protein among core autophagy-related (ATG) proteins. We previously found that ATG9A does not co-assemble into synaptophysin-positive vesicles, but rather, localizes to a distinct pool of vesicles within synapsin condensates in both fibroblasts and nerve terminals. The endocytic origin of these vesicles further suggests the existence of different intracellular sorting or segregation mechanisms for ATG9A and synaptophysin in cells. However, the precise underlying mechanism remains largely unknown. In this follow-up study, we investigated the endosomal localization of these two proteins by exploiting the advantages of a Rab5 mutant that induces the formation of enlarged endosomes. Notably, ATG9A and synaptophysin intermix perfectly and do not segregate on giant endosomes, indicating that the separation of these two proteins is not solely caused by the inherent properties of the proteins, but possibly by other unknown factors.

Background: Beneficial effects of whole-body vibration (WBV) on brain and musculoskeletal health in mice have been demonstrated, but underlying mechanisms remain relatively unrevealed. WBV improves attention and memory performance in mice, putatively through stimulation of the cholinergic system. Here, we investigated the effects of WBV on the septo-hippocampal cholinergic system. Methods: Young C57BL/6 mice (8 weeks old) were subjected to 10 min WBV/day (mechanical vibration: 30 Hz; ~0.1-µm peak-to-peak displacement), 5X/week for 5 weeks. In Experiment 1, choline acetyltransferase (ChAT)-immunoreactivity in the septum and hippocampus was analyzed either 2 or 24 h after the last WBV session. Pseudo-WBV-treated mice (same handling procedure as WBV, but no vibrations) served as controls. In Experiment 2, the longitudinal profile of ChAT-immunoreactivity was analyzed in the hippocampus after 1, 2, 3, 4, or 5 weeks of WBV. In addition, synaptophysin immunostaining was performed at either 2 and 5 weeks of WBV. Mice housed 1/cage during the entire experiment served as controls. The balance-beam test was used to monitor the functional impact of WBV. In Experiment 3, a Y-maze reference-memory test was performed after 5 weeks of WBV to obtain a functional cognitive outcome measure of WBV. Pseudo-WBV treated mice served as controls. Results: In Experiment 1, ChAT-immunoreactivity was significantly enhanced after the last WBV session of the 5-week period. This was found in the septum, Cornu Ammonis 1 (CA1), CA3, and dentate gyrus, and was dependent on layer and time-point (2 or 24 h). Experiment 2 revealed that, ChAT-immunoreactivity was lower after 2 weeks of WBV, whereas it was significantly higher after 5 weeks (similar to in Experiment 1). Immunostaining for synaptophysin, a marker for synaptic density, was also significantly higher after 5 weeks of WBV, but not significantly lower after 2 weeks, as was ChAT. WBV-treated groups performed significantly better than did controls on the balance beam from week 3 onwards. Experiment 3 showed that WBV-treated mice had better spatial-reference memory performance in the Y-maze test than did pseudo-WBV controls. Conclusions: Our results indicate that WBV stimulates the septo-hippocampal cholinergic system in a gradual and dynamic way that may contribute to improved spatial-memory performance. This finding suggests that WBV, by upregulation of the septo-hippocampal cholinergic system, may be considered a valuable therapeutic strategy to enhance brain functions in aging, neurodegenerative, and other brain diseases. [ABSTRACT FROM AUTHOR]

Introduction Neuroendocrine neoplasms (NENs) are heterogeneous group of neoplasms with relatively low incidence. Diagnosis of NENs requires an integrated approach of histology, immunohistochemistry, and molecular study. In the present study, we evaluated insulinoma-associated protein 1 (INSM1) expression in NENs and correlated it with other established neuroendocrine markers. Materials and Method Retrospective cross-sectional study was conducted in a tertiary care center. Consecutively, 100 cases from year November 2019 to January 2021 were enrolled in the study and all relevant data were noted. Results The mean (±standard deviation) age of the patients was 55.5 (±10.6) years with a male preponderance. Total 59% of the tumors were located in the lung of which 67% were poorly differentiated neuroendocrine carcinoma. INSM1 were positive in 97% cases, while synaptophysin (SYN) in 96% and chromogranin A (CgA) in 86%. Correlation of INSM1 expression with SYN and CgA was statistically significant (p -value < 0.05). Mean H-score of INSM1 was significantly higher than SYN and CgA and it was statistically significant (p -value < 0.001). Conclusion In the present study, the expression of INSM1 was seen in 97% cases of NENs. A statistically significant association was found between INSM1 and traditional NE markers. As a nuclear marker it is easy to interpret and it showed higher H-score. We conclude that INSM1 is a highly sensitive marker and recommend to incorporate it in the routine practice to aid in the diagnostic workup. However, a larger cohort is required to establish the organ-specific sensitivity and specificity of INSM1. [ABSTRACT FROM AUTHOR]

A 45‐year‐old woman with neurofibromatosis type 1 (NF1) developed a tumor in the left frontal lobe that showed features of giant cell glioblastoma (GC‐GB). In addition to the typical GC‐GB features, the tumor showed lipogenic differentiation, with many atypical lipoblasts and mature adipocytes. Tumor cells, including the lipogenic cells, were immunoreactive for GFAP, S‐100 protein, ATRX, and p53. They were negative for IDH1‐R132H, BRAF V600E, synaptophysin, NeuN, p16, mismatch repair proteins, and CD34. The patient is free from recurrence at approximately two years postoperatively. This is the fifth reported case of NF1‐associated GC‐GB (the second adult case). NF1 gene mutation might have played a role in the pathogenesis of lipogenic differentiation of GC‐GB. The differential diagnosis of lipidized GC‐GB from gliosarcoma or anaplastic pleomorphic xanthoastrocytoma is briefly discussed. [ABSTRACT FROM AUTHOR]

Although testicular tumors are the most common genital system tumors in dogs, Sertoli cells tumors (SCT) are the least occurring of them all to warrant their continuous evaluations. More so, SCTs may present some microscopic diagnostic difficulties requiring the use of other diagnostic tools. The present study focused on hematological, histomorphological and immunohistochemical evaluation of bilateral testicular growths in a Mongrel dog. All vital parameters were within optimum ranges and all investigations were according to standard procedures. The disease condition was characterized by lymphocytosis and thrombocytopenia with the rare bilateral grey to yellowish multilobulated testicular growths composed of diffuse haphazardly arranged uniform small round cells with scanty cytoplasm and hyperchromatic round to oval nuclei in a nest-like formation separated by little intercellular fibrillar septa, which reacted positively to only vimentin and NSE and also α-SMA (fibrillar septa only) but negatively to CD3, CD20, CD99, CK A1/A3, CD117, LCA, desmin, S-100, HMB45, β-HCG, E-cadherin, synaptophysin, and NFP antibodies, respectively. A diagnosis of bilateral canine SCT with tendency towards metastasis became imperative based on the study findings. Surgical excision of the mass was performed and managed. The used large battery of immunohistochemical antibodies highlighted their diagnostic potentials in aiding histopathological diagnosis of canine SCTs in veterinary practice. The findings further highlighted the need for the continuous monitoring of sexually active dogs with descended testis for cases of SCTs. [ABSTRACT FROM AUTHOR]

This article describes a case of a glioneuronal tumor with ATRX alteration, kinase fusion, and anaplastic features (GTAKA) in an adolescent patient. The tumor initially presented as a supratentorial ependymoma but rapidly disseminated to the leptomeninges within three months of surgery. The tumor exhibited specific genetic and epigenetic features of GTAKA, including loss of ATRX expression, a ZMIZ1::RET fusion, and a DNA methylation signature consistent with GTAKA. The case adds to the limited literature on this rare group of tumors and highlights the need for further research on their biological behavior and treatment options. [Extracted from the article]

In the present study, histopathological and immunohistochemical findings of olfactory ganglioneuroblastoma in a dog were compared to those of canine olfactory neuroepithelia and neuroblastomas. Olfactory ganglioneuroblastoma consists of ganglion cell-like tumor cells with Schwannian stroma and neuroblast-like tumor cells. Immunohistochemically, ganglion cell-like tumor cells were immunopositive for synaptophysin, β3-tubulin, and tyrosine hydroxylase, Schwannian stroma was immunopositive for GFAP and SOX2, and neuroblast-like tumor cells were immunopositive for OLIG2, β3-tubulin, SOX2, cytokeratin AE1/AE3, and p63. The immunohistochemical results of olfactory neuroepithelia and olfactory neuroblastomas were similar to those of neuroblast-like tumor cells. These results suggest that the ganglion cell-like tumor cells in the present case have a sympathetic neuron immunophenotype, whereas neuroblast-like tumor cells have an olfactory neuroepithelial immunophenotype. [ABSTRACT FROM AUTHOR]

FUS::CREM fusion is a distinct primary driver in rare neoplasms of the head and neck and other anatomic sites. Herein, we describe the clinicopathological, imaging, and molecular features of a malignant epithelioid mesenchymal neoplasm harboring FUS::CREM fusion, arising in the tongue of a 46-year-old male. Clinically, the patient presented with a left upper neck mass. Imaging revealed a 4.0 cm mass at the left base of tongue. Histologically, the tumor consisted of sheets of loosely cohesive, small round to ovoid cells with moderate cytoplasm, small nuclei with coarse chromatin, frequent nuclear pseudoinclusions, and dense peripheral lymphoplasmacytic and histiocytic infiltrates. Malignant features, including tumor necrosis, perineural invasion, and increased mitotic activity were observed; however, lymphovascular invasion was absent with no evidence metastatic disease in the examined lymph nodes. A comprehensive panel of immunohistochemical stains showed positivity for synaptophysin and ALK, with negative results for all other markers. RNA-based next-generation sequencing using anchored multiplex polymerase chain reaction (PCR) was performed and detected FUS::CREM fusion gene. The patient was treated by excision and postsurgical chemoradiation with no evidence of recurrence after four months. Additional cases supported by comprehensive clinical data collected over an extended period are necessary to precisely characterize epithelioid mesenchymal neoplasms harboring FUS::CREM fusion in the head and neck. [ABSTRACT FROM AUTHOR]

Introduction: Autism spectrum disorders (ASDs) are a group of neurodevelopmental disorders with poor social interaction, communication issues, aberrant motor movements, and limited repetitive interests and behaviour. Spirulina platensis (SP) contains several multi-nutrients and has a wide range of neuroprotective properties.Aim: The target of the current experiment is to detect the protective effects of S. platensis on valproic-induced autism in adult female albino rats’ siblings for the first time.Materials and Methods: Twelve Pregnant rats were separated into four main groups; Group I (control); Group II (S. platensis); Group III (autistic group); and Group IV (autistic SP-treated group). Fifteen offspring pups from each group were sacrificed, brain was divided for biochemical analysis as superoxide dismutase and malondialdehyde were evaluated spectrophotometrically while interleukin-6, interleukin-12, Bcl-2-associated X protein, B-cell lymphoma-2, Beclin-1, brain-derived neurotrophic factor were assessed by ELISA, other division of brain were used for gene expression of PI3k, Akt and mTOR pathway, last division of brain were stained using (H&E) and Giemsa stains. Tumour necrosis factor alpha (TNF-$\alpha \rpar$α) and Synaptophysin (SYN) markers were used for immunohistochemical staining.Results: Autistic Group (III) showed an increment in levels of MDA, IL-6, IL12 and BAX while showing a decrement in SOD, Bcl-2 and Beclin-1 as well as increased PI3k, Akt and mTOR gene expression. Autistic Group (III) also exhibited hypocellularity and disorganization of hippocampal and prefrontal cortex cells. The autistic SP-treated group (IV) showed improvement in these biochemical markers and pathological changes. Our findings suggest that Spirulina platensis will be significant in managing autism. [ABSTRACT FROM AUTHOR]

Members of the synaptophysin and synaptogyrin family are vesicle proteins with four transmembrane domains. In spite of their abundance in synaptic vesicle (SV) membranes, their role remains elusive and only mild defects at the cellular and organismal level are observed in mice lacking one or more family members. Here, we show that coexpression with synapsin in fibroblasts of each of the four brain-enriched members of this family--synaptophysin, synaptoporin, synaptogyrin 1, and synaptogyrin 3--is sufficient to generate clusters of small vesicles in the same size range of SVs. Moreover, mice lacking all these four proteins have larger SVs. We conclude that synaptophysin and synaptogyrin family proteins play an overlapping function in the biogenesis of SVs and in determining their small size. [ABSTRACT FROM AUTHOR]

Intercellular communication in the nervous system occurs through the release of neurotransmitters into the synaptic cleft between neurons. In the presynaptic neuron, the proton pumping vesicular- or vacuolar-type ATPase (V-ATPase) powers neurotransmitter loading into synaptic vesicles (SVs), with the V1 complex dissociating from the membrane region of the enzyme before exocytosis. We isolated SVs from rat brain using SidK, a V-ATPase–binding bacterial effector protein. Single-particle electron cryomicroscopy allowed high-resolution structure determination of V-ATPase within the native SV membrane. In the structure, regularly spaced cholesterol molecules decorate the enzyme’s rotor and the abundant SV protein synaptophysin binds the complex stoichiometrically. ATP hydrolysis during vesicle loading results in a loss of the V1 region of V-ATPase from the SV membrane, suggesting that loading is sufficient to induce dissociation of the enzyme. [ABSTRACT FROM AUTHOR]

Anti-N-methyl D-aspartate receptor (anti-NMDAR) encephalitis is an autoimmune disorder characterized by IgG antibodies targeting NMDAR. The prevalence is remarkably higher in women and some develop the condition during pregnancy. While immunotherapies have shown good outcomes for pregnant mothers and their infants, the impact on early neurodevelopment remains elusive. This study investigates the effects of anti-NMDAR antibody on the development of primary cortical cultures. Anti-NMDAR antibody was administered to the cultures at day in vitro 5 for the following 5 days to assess dendritic branching and arbor complexity, and at day in vitro 14 for measuring the expression of brain-derived neurotrophic factor (BDNF) and synaptic proteins. Immature cultured neurons treated with anti-NMDAR antibody exhibited impaired dendritic branching and arbor complexity. Interestingly, BDNF expression was unaffected in mature neurons. Additionally, GluN1 expression, a mandatory NMDAR subunit, was significantly reduced, while no significant alterations were observed in PSD-95, gephyrin and synaptophysin expression. These findings shed light on the structural and synaptic impacts of anti-NMDAR antibody on immature neurons, providing evidence for their consequences in early neuronal development. [ABSTRACT FROM AUTHOR]

A growing number of studies link dysfunction of macroautophagy/autophagy to the pathogenesis of diseases such as Alzheimer disease (AD). Given the global importance of autophagy for homeostasis, how its dysfunction can lead to specific neurological changes is puzzling. To examine this further, we compared the global deactivation of autophagy in the adult mouse using the atg7iKO with the impact of AD-associated pathogenic changes in autophagic processing of synaptic proteins. Isolated forebrain synaptosomes, rather than total homogenates, from atg7iKO mice demonstrated accumulation of synaptic proteins, suggesting that the synapse might be a vulnerable site for protein homeostasis disruption. Moreover, the deactivation of autophagy resulted in impaired cognitive performance over time, whereas gross locomotor skills remained intact. Despite deactivation of autophagy for 6.5 weeks, changes in cognition were in the absence of cell death or synapse loss. In the symptomatic APP PSEN1 double-transgenic mouse model of AD, we found that the impairment in autophagosome maturation coupled with diminished presence of discrete synaptic proteins in autophagosomes isolated from these mice, leading to the accumulation of one of these proteins in the detergent insoluble protein fraction. This protein, SLC17A7/Vglut, also accumulated in atg7iKO mouse synaptosomes. Taken together, we conclude that synaptic autophagy plays a role in maintaining protein homeostasis, and that while decreasing autophagy interrupts normal cognitive function, the preservation of locomotion suggests that not all circuits are affected similarly. Our data suggest that the disruption of autophagic activity in AD may have relevance for the cognitive impairment in this adult-onset neurodegenerative disease. Abbreviations: 2dRAWM: 2-day radial arm water maze; AD: Alzheimer disease; Aβ: amyloid-beta; AIF1/Iba1: allograft inflammatory factor 1; APP: amyloid beta precursor protein; ATG7: autophagy related 7; AV: autophagic vacuole; CCV: cargo capture value; Ctrl: control; DLG4/PSD-95: discs large MAGUK scaffold protein 4; GFAP: glial fibrillary acidic protein; GRIN2B/NMDAR2b: glutamate ionotropic receptor NMDA type subunit 2B; LTD: long-term depression; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; m/o: months-old; PNS: post-nuclear supernatant; PSEN1/PS1: presenilin 1; SHB: sucrose homogenization buffer; SLC32A1/Vgat: solute carrier family 32 member 1; SLC17A7/Vglut1: solute carrier family 17 member 7; SNAP25: synaptosome associated protein 25; SQSTM1/p62: sequestosome 1; SYN1: synapsin I; SYP: synaptophysin ; SYT1: synaptotagmin 1; Tam: tamoxifen; VAMP2: vesicle associated membrane protein 2; VCL: vinculin; wks: weeks. [ABSTRACT FROM AUTHOR]

Stimulation of the calcium‐sensing receptor (CaSR) regulates vascular contractility, but cellular mechanisms involved remain unclear. This study investigated the role of perivascular sensory nerves in CaSR‐induced relaxations of male rat mesenteric arteries. In fluorescence studies, colocalisation between synaptophysin, a synaptic vesicle marker, and the CaSR was present in the adventitial layer of arterial segments. Using wire myography, increasing external Ca2+ concentration ([Ca2+]o) from 1 to 10 mM induced vasorelaxations, previously shown to involve the CaSR, which were inhibited by pretreatment with capsaicin. [Ca2+]o‐induced vasorelaxations were partially reduced by the calcitonin gene‐related peptide (CGRP) receptor blockers, CGRP 8–37 and BIBN 4096, and the neurokinin 1 (NK1) receptor blocker L733,060. The inhibitory effect of CGRP 8–37 required a functional endothelium whereas the inhibitory action of L733,060 did not. Complete inhibition of [Ca2+]o‐induced vasorelaxations occurred when CGRP 8–37 and L733,060 were applied together. [Ca2+]o‐induced vasorelaxations in the presence of capsaicin were abolished by the ATP‐dependent K+ channel (KATP) blocker PNU 37883, but unaffected by the endothelium nitric oxide synthase (eNOS) inhibitor L‐NAME. We suggest that the CaSR on perivascular sensory nerves mediate relaxations in rat mesenteric arteries via endothelium‐dependent and ‐independent mechanisms involving CGRP and NK1 receptor‐activated NO production and KATP channels, respectively. [ABSTRACT FROM AUTHOR]

Breast cancer is the most common type of cancer of the female gender. A rare subtype of breast cancer is the invasive breast carcinoma (IBC) with neuroendocrine (NE) differentiation. Its incident is believed to be 0.1% to 5% of all breast cancers. We report a rare case of a 66-year old woman who presented with an isolated nodule of the left breast. The patient underwent modified radical mastectomy. Pathology revealed invasive breast carcinoma with neuroendocrine differentiation. Invasive breast carcinoma is an extremely rare group of neoplasms, the exact frequency of which cannot be determined with current data. Therefore, it is necessary for future studies to focus on the pathophysiology of this subtype of breast cancer and on the potential therapeutic approaches. [ABSTRACT FROM AUTHOR]

Memory problems are often the first signs of cognitive impairment related to Alzheimer's disease (AD), and stem cells and stem cell-derived exosomes (EXOs) have been studied for their therapeutic potential to improve the disease signs. While many studies have shown the anti-inflammatory and immunomodulatory effects of stem cells and exosomes on improving memory in different AD models, there is still insufficient data to determine how they modulate neural plasticity to enhance spatial memory and learning ability. Therefore, we conducted a study to investigate the effects of exosomes derived from 3D-cultured human Unrestricted Somatic Stem Cells (hUSSCs) on spatial memory and neuroplasticity markers in a sporadic rat model of AD. Using male Wistar rats induced by intracerebral ventricle injection of streptozotocin, we demonstrated that intranasal administration of hUSSC-derived exosomes could decrease Aβ accumulation and improve learning and memory in the Morris water maze test. We also observed an increase in the expression of pre-synaptic and post-synaptic molecules involved in neuronal plasticity, including NMDAR1, integrin β1, synaptophysin, pPKCα, and GAP-43, in the hippocampus. Our findings suggest that intranasal administration of exosomes can ameliorate spatial learning and memory deficits in rats, at least in part, by increasing the expression of neuroplasticity proteins. These results may encourage researchers to further investigate the molecular pathways involved in memory improvement after stem cell and exosome therapy, with the goal of increasing the efficacy and safety of exosome-based treatments for AD. [ABSTRACT FROM AUTHOR]

Duchenne muscular dystrophy (DMD) is the most common type of muscular dystrophy, but the spinal cord is rarely examined. Here we report a case of DMD with interesting spinal cord findings. In a 37-year-old man with DMD accompanied by hypoxic encephalopathy from the age of 32 years, autopsy showed amyotrophic lateral sclerosis-like pyramidal tract degeneration over the entire spinal cord, presumably due to hypoxic encephalopathy. Furthermore, anterior horn cells exhibited Wallerian degeneration-like changes. To investigate more about the pathogenesis, an immunohistochemical study using anti-synaptophysin, glutamic acid decarboxylase (GAD), postsynaptic density protein-95 (PSD-95) and choline acetyltransferase (ChAT) antibodies was performed. Immunostaining for synaptophysin showed that the number of synapses around anterior horn cell were decreased, contrary to the finding of teenage DMD, in which the number of synapses were increased, probably due to the reaction toward the reduced anterior horn cell activity. The decrease of synapses of the present case may be mainly due to hypoxic encephalopathy, based on the degeneration of the pyramidal tract. Another interesting finding is that GAD was strongly positive in the cytoplasm of anterior horn cells, which may be explained by Wallerian degeneration-like mechanism. Moreover, the expression of PSD-95 is increased in anterior horn cells. Compensation for postsynaptic damage can be considered, since dystrophin is necessary for maintaining the post-synaptic maintenance. There were no apparent differences in ChAT immunostaining. Further investigation is necessary whether these findings are characteristic of long-term surviving cases accompanied by hypoxic encephalopathy.

Background. Stressful influences, depending on their severity and duration, can cause the development of pathological conditions. Repeated episodes of stress cause functional and structural changes in the central nervous system and can cause the development of depressive conditions. Depression is one of the leading mental illnesses. One of the most stress-sensitive brain structures is the hippocampus. Objective. To study is to evaluate structural changes in the hippocampus, which is considered as a heterogeneous structure with separate dorsal and ventral regions, to evaluate the expression of inducible nitric oxide synthase, endothelial nitric oxide synthase, serine racemase, synaptophysin in a mild stress model.Methods. A study of the effects of mild stress was carried out on 16 adult male Wistar rats (age 12 months, body weight 350–400 g). After acclimatization, the rats were divided into two equal groups (n = 8): intact (control) and stressed. When keeping animals, modeling and removing them from the experiment, we were guided by the Regulations for Carrying Out Work Using Laboratory Animals and the Declaration of Helsinki. Experimental modeling of depression in animals was induced by mild stress exposure for 7 days (30 minutes daily). Euthanasia was performed in a CO2 incubator. The brain was fixed in neutral buffered 10% formalin. Paraffin sections were made in the frontal plane, stained with hematoxylin and eosin, thionin using the Nissl method and examined at a level from –2.40 to –3.96 mm relative to bregma using an Axio Lab A1 microscope (Carl Zeiss Microscopy GmbH, Germany). Photo documentation was carried out with an AxioCam 105 color camera (Carl Zeiss Microscopy GmbH, Germany). Using the Image Analysis module of the ZEN 1.1.2.0 program (Carl Zeiss Microscopy GmbH, Germany) in the pyramidal layer of the hippocampus. Statistical analysis was performed with Microsoft Office Excel 2016 (Microsoft, USA) and Prism 6 (GraphPad Software Inc., USA). Comparisons of two conditions were made by nonparametric Mann-Whitney-U test to avoid a statistical bias of unequal data distribution. The level of significance was set at p < 0.05. The summarized data were presented as a as mean ± standard error of mean.Results. Functional research methods and assessment of pathological changes in hippocampal neurons are presented. An increase in the relative number of wrinkled hyperchromatic pyramidal neurons in the dorsal cornu ammonis field 3 in stressed rats was noted by 23.6% (p < 0.05) compared to the control. There was an increase in the relative number of inducible nitric oxide synthase-immunopositive neurons in the dorsal cornu ammonis field 3 by 40% ( p < 0.05) and the relative area of inducible nitric oxide synthase-immunoreactive material by 35% (p < 0.05) in the pyramidal layer of cornu ammonis field 3 in stressed rats. A decrease in the relative area of synaptophysin-immunopositive material in stressed rats was found in the ventral cornu ammonis field 3 compared to the control group by 16.8% (p < 0.05); decrease in the relative area of serine racemase-immunopositive material in dorsal cornu ammonis field 3 by 4.3% (p < 0.05) and ventral cornu ammonis field 3 by 7.8% (p < 0.05).Conclusion. The results of the study demonstrate that mild stress is an adequate model of depression in rats. In animals exposed to mild stress, pronounced morphological signs of damage to hippocampal neurons were revealed; motor and indicative exploratory activity decreases. Differences were found in morphofunctional changes in the dorsal and ventral parts of the hippocampus under the influence of mild stress. In cornu ammonis field 3 of the dorsal hippocampus, in contrast to the ventral section, more pronounced signs of damage to pyramidal layer neurons were observed. The increase in the relative number of inducible nitric oxide synthase-immunopositive neurons and the relative area of inducible nitric oxide synthase-immunoreactive material in the cornu ammonis field 3 pyramidal layer in stressed rats indicates an increase in nitric oxide production and the participation of nitrooxide-dependent free radical mechanisms of damage to hippocampal neurons. The decrease in the relative area of synaptophysin-immunoreactive material in stressed rats may contribute to changes in synaptic plasticity. A decrease in the relative area of serine racemase-immunoreactive material in the dorsal and ventral parts of cornu ammonis field 3 is considered to be a sign of a possible decrease in N-methyl-D-aspartate-dependent neurotransmission in the hippocampus under stress.

Prostate cancer has heterogeneous growth patterns, and its prognosis is the poorest when it progresses to a neuroendocrine phenotype. Using bioinformatic analysis, we evaluated RNA expression of neuroendocrine genes in a panel of five different cancer types: prostate adenocarcinoma, breast cancer, kidney chromophobe, kidney renal clear cell carcinoma and kidney renal papillary cell carcinoma. Our results show that specific neuroendocrine genes are significantly dysregulated in these tumors, suggesting that they play an active role in cancer progression. Among others, synaptophysin (SYP), a conventional neuroendocrine marker, is upregulated in prostate adenocarcinoma (PRAD) and breast cancer (BRCA). Our analysis shows that SYP is enriched in small extracellular vesicles (sEVs) derived from plasma of PRAD patients, but it is absent in sEVs derived from plasma of healthy donors. Similarly, classical sEV markers are enriched in sEVs derived from plasma of prostate cancer patients, but weakly detectable in sEVs derived from plasma of healthy donors. Overall, our results pave the way to explore new strategies to diagnose these diseases based on the neuroendocrine gene expression in patient tumors or plasma sEVs.

Objective: To .study the improving effect of Anemarrhenae Rhizoma-Phellodendri Chinensis Cortex herb pair(Zhi Bai) on cognitive impairment in D-galactose(D-gal) administered mice, and to explore the mechanism of Zhi Bai in improving cognitive impairment through the AMPK/mTOR signaling pathway. Methods: Seventy-five C57BL/6J mice were randomly divided into five groups: the control group, the model group (D-gal 125 mg/kg), the piracetam group (468 mg/kg), the Zhi Bai group (4.5 g/kg), and the mTOR inhibitor group (everolimus, RAD001, 3 mg/kg), with 15 mice in each group. The aging mouse model was established using D-gal, followed by 8 weeks of oral administration of Zhi Bai decoction. Cognitive functions in aging mice were assessed using the Morris water maze and novel object recognition tests. Hippocampal tissue pathology was observed using hematoxylin and eosin (H& E) staining; neuronal and synaptic pathological morphology in the hippocampal region was examined with Nissl and Golgi staining. Hippocampal tissues were collected to determine the levels of adenosine triphosphate (ATP) in the brain. The protein expression levels of ubiquitin-binding protein 62 (P62), Beclin-1 associated with myosin, light chain kinase BCL2 (Beclin-1), synaptophysin (Syn), postsynaptic density protein-95 (PSD-95), AMP-activated protein kinase (AMPK), and mTOR in the hippocampus were detected by Western blot. The gene expression levels of Syn, AMPK, and mTOR in the hippocampus were measured using quantitative real-time PCR (qRT-PCR). Results: Compared to the control group, the model group mice showed significant cognitive impairment in the Morris water maze and novel object recognition tests (P<0.01). In the model group, there was a reduction in cell numbers, loose cell arrangement, and irregular neuronal morphology, a significant decrease in Nissl bodies, and a decrease in dendritic branch and spine density in the hippocampal region. ATP levels, as well as P62, Syn, PSD-95, and mTOR protein expressions in the hippocampus of the model group, were significantly reduced (P<0.01), while Beclin-1 expression was significantly increased (P<0.01). The ratio of pAMPK to AMPK protein content and the expression of AMPK genes were significantly elevated (P<0.01), whereas Syn and mTOR gene expressions were significantly decreased (P<0.01). Compared to the model group, cognitive function was significantly improved in the piracetam and Zhi Bai groups, as evidenced by a significant reduction in the latency period in the Morris water maze test (P<0.01), increased platform crossing numbers and target quadrant dwell time (P<0.01), and a significant increase in the novel object recognition index (P< 0.01). Dendritic spine density in the hippocampal region was significantly increased (P<0.01), and neuronal damage was alleviated to some extent. ATP levels and P62, Syn, PSD-95, and mTOR protein expressions in the hippocampus were significantly increased (P<0.01, P<0.05), Beclin-1 protein expression was significantly reduced (P<0.01), and the ratio of pAMPK to AMPK protein content and AMPK gene expression were significantly decreased (P<0.01, P<0.05), with Syn and mTOR gene expressions significantly elevated (P<0.01). The results for the RAD001 inhibitor group were similar to the model group, but Zhi Bai treatment led to a recalibration of these indicators. Conclusion: Zhi Bai may inhibit excessive autophagy of neurons, enhance synaptic plasticity and improve D-gal-induced cognitive impairment in mice by activating the AMPK/mTOR signaling pathway. [ABSTRACT FROM AUTHOR]

Aims/Introduction: Defective insulin signaling in the brain may disrupt hippocampal neuroplasticity resulting in learning and memory impairments. Thus, this study investigated the effect of aerobic exercise training on cognitive function and synaptic protein markers in diabetic rats. Materials and methods: Twenty male Wistar rats (200–250 g), were fed on high-fat diet and received a low dose of streptozotocin (35 mg/kg, i.p) to induce type 2 diabetes. Then diabetic animals were randomly divided into sedentary and training groups. The exercise training program was treadmill running at 27 m/min for 60 min/day for 8 weeks. One day after the last training session, Morris Water Maze (MWM) task was performed to evaluate spatial learning and memory. Then, the hippocamp and prefrontal cortex tissues were instantly dissected for immunoblotting assay of BDNF, GSK-3β, p-GSK-3β, P38, p-P38, ERK1/2, p-ERK1/2, heat shock protein-27 (HSP27), SNAP-25, synaptophysin, and PSD-95. Independent t-test analysis and two-way ANOVA was used to determine the differences under significance level of 0.05 using the 26th version of IBM SPSS statistical software. Results: The results showed that aerobic exercise improved memory as assessed in the MWM task. Moreover, aerobic exercise up-regulated HSP27 and BDNF protein levels in the prefrontal cortex, and hippocampus coincided with robust elevations in SNAP25 and PSD-95 levels. Moreover, exercise reduced phosphorylated P38, while increased p-ERK1/2 and p-GSK-3β (p). Conclusion: Our findings suggest that aerobic exercise may debilitate the harmful effects of diabetes on the cognitive function possibly through enhancing synaptic protein markers. [ABSTRACT FROM AUTHOR]

Background: Tanshinone IIA (TSIIA) is an element of the effective ingredients of Salvia miltiorrhiza Bunge (Labiatae), exhibits a significant therapeutic effect in brain neuroprotection. The focus of this study was the examination of synaptic plasticity of in Mg2+-free-induced epileptic hippocampus neurons and how TSIIA protects against it. Methods: The purity of the primary hippocampal neurons extracted from Sprague Dawley rats was assessed within 24 hours by microtubule-associated protein (MAP2) immunofluorescence staining. A hippocampal neuron model for Mg2+-free-induced spontaneous recurrent epileptiform discharge was developed, five experimental groups were then randomized: blank (Blank), model (Model), TSIIA (TSIIA, 20 µM), LY294002 (LY294002, 25 µM), and TSIIA+LY294002 (TSIIA+LY294002, 20 µM+25 µM). FIJI software was used to examine variations of neurite complexity, total length of hippocampal neurons, number of primary dendrites and density of dendritic spines. Developmental regulation brain protein (Drebrin) and brain-derived neurotrophic factor (BDNF) expression was evaluated using immunofluorescence staining and the relative expression of phospho-protein kinase B (p-Akt)/Akt, BDNF, synaptophysin (SYN) and postsynaptic density 95 (PSD-95) determined by Western blot. Results: In contrast to the model group, TSIIA drastically reduced damage to synaptic plasticity of hippocampal neurons caused by epilepsy (p < 0.05). The TSIIA group showed a significant increase in the relative expression of PSD-95, SYN, BDNF, and p-Akt/Akt (p < 0.01). Conclusions: TSIIA was effective in reducing harm to the synaptic plasticity of hippocampal neurons induced by persistent status epilepticus, with the possible mechanism being regulation of the phosphatidylinositol 3-kinase 56 (PI3K)/Akt signaling pathway. [ABSTRACT FROM AUTHOR]

Background: Stroke is an acute cerebrovascular disease in which brain tissue is damaged due to sudden obstruction of blood flow to the brain or the rupture of blood vessels in the brain, which can prompt ischemic or hemorrhagic stroke. After stroke onset, ischemia, hypoxia, infiltration of blood components into the brain parenchyma, and lysed cell fragments, among other factors, invariably increase blood–brain barrier (BBB) permeability, the inflammatory response, and brain edema. These changes lead to neuronal cell death and synaptic dysfunction, the latter of which poses a significant challenge to stroke treatment. Results: Synaptic dysfunction occurs in various ways after stroke and includes the following: damage to neuronal structures, accumulation of pathologic proteins in the cell body, decreased fluidity and release of synaptic vesicles, disruption of mitochondrial transport in synapses, activation of synaptic phagocytosis by microglia/macrophages and astrocytes, and a reduction in synapse formation. Conclusions: This review summarizes the cellular and molecular mechanisms related to synapses and the protective effects of drugs or compounds and rehabilitation therapy on synapses in stroke according to recent research. Such an exploration will help to elucidate the relationship between stroke and synaptic damage and provide new insights into protecting synapses and restoring neurologic function. [ABSTRACT FROM AUTHOR]

Introduction. Triple negative breast carcinomas are characterized by a lack of hormone receptor and HER2 expression and inconsistent expression of breast-specific immunohistochemical markers. The expression of many site-specific markers in these tumors is largely unknown. The objective of the study was to examine the expression of widely used immunohistochemical markers on a large cohort of triple negative breast cancer. Methods. Sections from tissue microarrays were stained with 47 markers using routine protocols. Most markers were scored using a modified Allred method. ATRX, BAP1, SMAD4, e-cadherin, and beta-catenin were scored as retained or lost. Mammaglobin was considered positive if there was at least moderate intensity staining in any tumor cells. P16 was scored as overexpressed or not overexpressed; p53 was scored as wildtype, overexpressed, null, or cytoplasmic. Results. The cohort consisted of 639 tumors including 601 primary and 32 metastases. Overall, 96% expressed GATA3, mammaglobin, and/or SOX10 while 97% of no special type tumors expressed this panel. Carcinoma of apocrine differentiation demonstrated an AR positive, SOX10 negative, K5 negative/focal immunophenotype. PAX8 (SP348), WT1, Napsin A, and TTF1 (8G7G3/1) were never or rarely expressed while CA9, CDX2, NKX3.1, SATB2 (SATBA410), synaptophysin, and vimentin were variably expressed. Conclusions. Almost all TNBC express at least 1 of the 3 IHC markers: GATA3, mammaglobin, and/or SOX10. Carcinoma of apocrine differentiation is characterized by an AR positive, SOX10 negative, K5 negative or focal immunophenotype. Cautious interpretation of so-called site-specific markers, with knowledge of antibody clones, is required in excluding the diagnosis of triple negative breast cancer. [ABSTRACT FROM AUTHOR]

The study was aimed to determine of the most significant pathomorphological signs of severe hepatic encephalopathy (HE) in deceased cirrhotic patients with acute-on-chronic liver failure (ACLF) syndrome based on changes of the glioneuronal complex and the level of tissue ammonia. Using pathohistological, histochemical, and immunohistochemical methods, the cerebral cortex, thalamus, striatum, and cerebellum of 21 deceased patients with acutely decompensated liver cirrhosis with ACLF syndrome and HE Grade 3-4 were examined in comparison with control group, which included 30 deceased patients from acute cardiovascular failure. The study revealed that during HE Grade 3-4 as a component of ACLF, in all studied brain regions, there was a reliably (p<0.05) higher histochemical level of tissue ammonia (up to 500%), increased numbers (up to 215.69%) of apoptotic neurons (according to caspase-3), reduced (up to 119.60%) level of synaptophysin, increased expression of glutamine synthetase (up to 253.02%) and aquaporin-4 (up to 481.81%) associated by reduced (up to 296.81%) expression of glial fibrillary acidic protein in astrocytes, increased (up to 11-fold) numbers of Alzheimer type 2- astrocytes, expansion of perivascular and pericellular «edematous» spaces (up to 890.81%), increased numbers of amyloid bodies (up to 5-fold), increased area of immunopositive material of CD68+ microgliocytes (up to 114.78%) with an increase (up to 71.91%) in the proportion of CD68+ amoeboid microglia. The above-mentioned changes confirm that the loss of consciousness and other psychoneurological manifestations of severe HE Grade 3-4 are due to compound ammonia-associated changes in the components of the glioneuronal complex, namely: adaptive remodeling and dystrophic changes in astrocytes, reduced synaptic transmission and apoptotic neuronal death, reactive changes in microglia with a small proportion of microgliocytes involved in phagocytosis, cytotoxic brain edema and dysfunction of the glymphatic system. [ABSTRACT FROM AUTHOR]

Colorectal cancer (CRC) is one of the main causes of cancer‐related deaths. However, the surgical control of the CRC progression is difficult, and in most cases, the metastasis leads to cancer‐related mortality. Mesenchymal stem/stromal cells (MSCs) with potential translational applications in regenerative medicine have been widely researched for several years. MSCs could affect tumor development through secreting exosomes. The beneficial properties of stem cells are attributed to their cell–cell interactions as well as the secretion of paracrine factors in the tissue microenvironment. For several years, exosomes have been used as a cell‐free therapy to regulate the fate of tumor cells in a tumor microenvironment. This review discusses the recent advances and current understanding of assessing MSC‐derived exosomes for possible cell‐free therapy in CRC. Significant statement: The current analysis explores the potential contribution of mesenchymal stem/stromal cells in colorectal cancer through the release of extracellular vesicles. These vesicles' contents play a significant role in fostering tumor microenvironments, stimulating cancer cell proliferation, prompting stromal cell differentiation, encouraging angiogenesis, fostering premetastatic niche establishment, and facilitating invasion. Additionally, extracellular vesicles play a crucial role in modulating immune system responses and influencing resistance to anticancer treatments, such as chemotherapy and targeted agents. Beyond their role in promoting cancer advancement, these vesicles also contribute to cell invasion and metastasis, making them potential biomarkers for monitoring cancer progression. Consequently, both mesenchymal stem/stromal cells and their extracellular vesicles hold promise as prospective cell‐free therapies in the context of colorectal cancer. [ABSTRACT FROM AUTHOR]

We report a case of a 55‐year‐old female with an asymptomatic pink–brown nodule. Histological examination demonstrated a composite haemangioendothelioma with positive synaptophysin staining. [ABSTRACT FROM AUTHOR]

This study was investigated to examine the neuroprotective effect of fermented Protaetia brevitarsis larvae (FPB) in ethanol-induced-dementia mice. Consumption of FPB by mice resulted in improved memory dysfunction in the Y-maze, passive avoidance, and Morris water maze tests. FPB significantly decreased oxidative stress by regulating levels of malondialdehyde (MDA), superoxide dismutase (SOD), and reduced glutathione (GSH) in brain tissues. In addition, FPB restored cerebral mitochondrial dysfunction by modulating levels of reactive oxygen species (ROS), mitochondrial membrane potential (MMP), and ATP. In addition, FPB enhanced the cholinergic system via the regulation of acetylcholine (ACh) content, acetylcholinesterase (AChE) activity, and expressions of AChE and choline acetyltransferase (ChAT) in brain tissues. FPB ameliorated neuronal apoptosis through modulation of the protein kinase B (AKT)/B-cell lymphoma (BCL)-2 signaling pathway. Also, FPB improved inflammation response by down-regulating the toll-like receptor (TLR)-4/nuclear factor (NF)-κB pathway. Additionally, FPB ameliorated synaptic plasticity via the increase of the expressions of synaptophysin (SYP), postsynaptic density protein (PSD)-95, and growth-associated protein (GAP)-43. Treatment with FPB also reinforced the blood–brain barrier by increasing tight junctions including zonula occludens (ZO)-1, occludin, and claudin-1. In conclusion, these results show that FPB can improve cognitive impairment via AKT/NF-κB pathways in ethanol-induced-dementia mice. [ABSTRACT FROM AUTHOR]

Background/Aim: Given that gastric small cell neuroendocrine carcinoma (SCNEC) is notably more aggressive than conventional adenocarcinoma, and a platinum-based regimen aligned with the treatment for pulmonary SCNEC is advocated when chemotherapy is needed, ensuring an accurate pathological diagnosis is paramount. Case Report: A 63-year-old man, examined for melena, underwent gastroscopy which revealed a total circumferential Borrmann type 3 lesion extending from the pylorus to the antrum of the stomach. He underwent a distal gastrectomy with D2 lymphadenectomy. The microscopic examination revealed SCNEC with a minor adenocarcinoma component. Immunohistochemically, the SCNEC was diffusely positive for synaptophysin, CD56, and INSM1, very focally positive for chromogranin A, and negative for leukocyte common antigen, CD3, and CD20. A significant observation in this case was the complete negativity for epithelial markers including keratin (CK7, CK8, CK20, CAM5.2, and AE1/AE3) and epithelial membrane antigen. Conclusion: Diffuse positivity for neuroendocrine markers, negativity for other lineage markers, and a transition from the adenocarcinoma component, if present, serve as significant diagnostic clues for gastric SCNEC with loss of epithelial markers expression. SCNEC should not be excluded solely based on the negative result for epithelial markers. [ABSTRACT FROM AUTHOR]

Glutamate is a major excitatory neurotransmitter that mediates neuronal damage in acute and chronic brain disorders. The effect and mechanism of phillygenin, a natural compound with neuroprotective potential, on glutamate release in isolated nerve terminals (synaptosomes) prepared from the rat cerebral cortex were examined. In this study, 4-aminopyridine (4-AP), a potassium channel blocker, was utilized to induce the release of glutamate, which was subsequently quantified via a fluorometric assay. Our findings revealed that phillygenin reduced 4-AP-induced glutamate release, and this inhibitory effect was reversed by removing extracellular Ca2+ or inhibiting vesicular transport with bafilomycin A1. However, exposure to the glutamate transporter inhibitor dl-threo-beta-benzyl-oxyaspartate (dl-TOBA) did not influence the inhibitory effect. Moreover, phillygenin did not change the synaptosomal membrane potential but lowered the 4-AP-triggered increase in intrasynaptosomal Ca2+ concentration ([Ca2+]i). Antagonizing Cav2.2 (N-type) calcium channels blocked the inhibition of glutamate release by phillygenin, whereas pretreatment with the mitochondrial Na+/Ca2+ exchanger inhibitor, CGP37157 or the ryanodine receptor inhibitor, dantrolene, both of which block intracellular Ca2+ release, had no effect. The effect of phillygenin on glutamate release triggered by 4-AP was completely abolished when MAPK/ERK inhibitors were applied. Furthermore, phillygenin attenuated the phosphorylation of ERK1/2 and its major presynaptic target, synapsin I, a protein associated with synaptic vesicles. These data collectively suggest that phillygenin mediates the inhibition of evoked glutamate release from synaptosomes primarily by reducing the influx of Ca2+ through Cav2.2 calcium channels, thereby subsequently suppressing the MAPK/ERK/synapsin I signaling cascade. [ABSTRACT FROM AUTHOR]

PurposeTo highlight the clinical, neuroradiographic, neuropathologic, and molecular features of histologically identified neurocytoma in a pediatric cohort and highlight the evolving use methylation profiling in providing diagnostic clarity in difficult to diagnosis pediatric brain tumors.MethodsFive consecutive children (ages 9-13, 2 girls 3 boys) were histologically diagnosed with neurocytoma at Rady Children's Hospital San Diego from 2012 to 2018. Clinical and molecular features were analyzed with regards to treatment course and outcome.ResultsPresenting symptoms included seizures (n = 2), syncope (n = 1), headache (n = 2), visual disturbances (n = 2) and emesis (n = 2). Tumor location included intraventricular (n = 2), intraventricular with parenchymal spread (n = 1), and extraventricular (n = 2). Magnetic resonance imaging demonstrated reduced diffusivity (2/5), signal abnormality on susceptibility-weighted sequences (3/5), and varying degrees of contrast enhancement (4/5). All patients underwent surgical resection alone. Recurrence occurred in four children that were treated with surgery (4/4), adjuvant radiation (2/4), and chemoradiation (1/4). Neuropathologic features included positivity for GFAP (4/5), synaptophysin (4/5), NSE (2/2), NeuN (4/4), and variable Ki-67 (

Objective To report a case of primary neuroendocrine breast cancer (NEBC)，and to provide clinical reference for the diagnosis and treatment of the disease. Methods The diagnosis and treatment process of a 54-year-old female patient with NEBC admitted to Jiangsu Province Hospital of Chinese Medicine on September 13, 2021 was retrospectively reported，and analyzed in combination with relevant literature. Results The patient was admitted due to unilateral painless breast mass. The patient was considered to have a non-special type of breast cancer with neuroendocrine differentiation and underwent surgery. The diagnosis of NEBC was confirmed by pathology and immunohistochemistry after operation. Further comprehensive treatment was given and no local recurrence or distant metastasis was found in the 1-year follow-up. Conclusion NEBC is a rare and special type of breast carcinoma which lacks specific clinical manifestations. Pathology and immunohistochemistry are required for diagnosis. Chromogranin A (CgA) and sunaptophysin (Syn) are generally considered to be reliable markers for the diagnosis of NEBC. The treatment plan has not yet formed a unified standard. Treatment guidelines for general type of breast cancer of the same pathological stage are mostly referred to. There is still no consensus on its prognosis.

Background and purpose: Stress is a stimulus that leads to a physical or psychological reaction. Stress affects memory and cognition. Common drugs for treating stress and memory disorders have limited effects and many side effects, so the search for new effective compounds with natural origin and fewer side effects is of interest. Various studies have shown that Terminalia chebula) T. chebula (and crocin are effective in improving memory. Several proteins, including synapsin-1, synaptophysin, and PSD95, are involved in the transmission of nerve messages in synapses involved in memory. In this study, the effect of the hydroalcoholic extract of T. chebula and crocin in improving memory and stress and the expression of synaptophysin, PSD 95, and synapsin-1 genes in the hippocampal tissue of male rats of the immobility stress model has been evaluated. Materials and methods: 25 adult male Wistar rats were randomly divided into five groups, including a control group, a stress group, treated with hydroalcoholic extract of T. chebula group, treated with crocin group, simultaneously treated with hydroalcoholic extract of T. chebula, and crocin group. All groups except the control group were subjected to immobility stress for 14 days. Crocin was injected intraperitoneally (30 mg/kg) and hydroalcoholic extract of T. chebula was given as intragastric gavage (50 mg/kg). After fourteen days, the shuttle box test was performed to check the memory, then the animals were anesthetized and their hippocampal tissue was isolated, and the expression changes of synapsin-1, synaptophysin, and PSD 95 genes in the tissue were analyzed by Real-time PCR method. Results: Immobility stress caused disruption in two memory indicators, i.e. increased the duration of staying in the dark chamber (P˂0.01) and decreased the latency time to enter the dark chamber compared to the control group (P˂0.0001). Treatment with the alcoholic extract of T. chebula did not affect the duration of staying in the dark chamber (P>0.05), but crocin decreased it compared to the stress group (P˂0.05). The hydroalcoholic extract of T. chebula and crocin increased the latency time to enter the dark chamber compared to the stress group (P˂0.01 and P˂0.001, respectively). As a result, both of them affected memory improvement parameters. The combination of the hydroalcoholic extract of T. chebula and crocin decreased the duration of staying in the dark chamber (P˂0.05) and increased the latency time to enter the dark chamber compared to the stress group (P˂0.001). Also, Immobility stress decreased the expression of synaptophysin, synapsin-1, and PSD95 genes in the hippocampus tissue compared to the control group (P˂0.001 for all genes). The expression of synaptophysin, synapsin-1, and PSD95 genes in the hippocampus tissue of groups treated with hydroalcoholic extract of T. chebula (P˂0.01, P˂0.01 and P˂0.001, respectively), crocin (P˂0.001, P˂0.01 and P˂0.001, respectively), and their combination (P˂0.001, P˂0.001 and P˂0.01, respectively), increased compared to the stress group. Conclusion: treatment with crocin and hydroalcoholic extract of T. chebula separately or their combination was effective in improving memory and reducing stress by increasing the expression of synapsin 1, synaptophysin, and PSD95 genes.

Abstract Introduction NUT carcinoma is a rare cancer associated with a poor prognosis. Because of its rarity, its diagnosis is challenging and is usually made by excluding other diagnoses. Immunohistochemical analysis is a reliable technique that contributes to a correct diagnosis, but overestimating the expression of neuroendocrine (NE) markers may result in an incorrect diagnosis. In this study, we established the immunohistochemical phenotypes of NUT carcinoma compared with tumors that mimic its phenotype to identify potential diagnostic pitfalls. Methods Eight cases of NUT carcinoma were examined along with eight basaloid squamous cell carcinomas and thirteen cases of small cell carcinoma using an immunohistochemical panel consisting of various antibodies. Results Of the eight NUT carcinomas, three patients had a smoking history. All the cases examined for INSM1 were positive (6/6, 100%), although the staining was somewhat weak. Among the NE markers, synaptophysin was variably positive in two NUT carcinomas (2/6, 33%); however, all cases were negative for ASCL1, chromogranin A, and CD56. Moreover, the squamous cell markers, p40 and CK5/6, were weakly expressed in 4/6 (67%) and 3/6 (50%) of the NUT carcinomas, respectively. Conclusions For tumors with an ambiguous morphology, applying the neuroendocrine phenotype of NUT carcinoma may be misleading; particularly, when distinguishing it from small-cell carcinoma. Similarly, null or weak expression of squamous cell markers may be observed in NUT carcinoma, but this differs from squamous cell carcinoma, which consistently demonstrates strong positivity for squamous cell markers.

Abstract Regional differences in synaptic degeneration may underlie differences in clinical presentation and neuropathological disease progression in Parkinson’s Disease (PD) and Dementia with Lewy bodies (DLB). Here, we mapped and quantified synaptic degeneration in cortical brain regions in PD, PD with dementia (PDD) and DLB, and assessed whether regional differences in synaptic loss are linked to axonal degeneration and neuropathological burden. We included a total of 47 brain donors, 9 PD, 12 PDD, 6 DLB and 20 non-neurological controls. Synaptophysin+ and SV2A+ puncta were quantified in eight cortical regions using a high throughput microscopy approach. Neurofilament light chain (NfL) immunoreactivity, Lewy body (LB) density, phosphorylated-tau and amyloid-β load were also quantified. Group differences in synaptic density, and associations with neuropathological markers and Clinical Dementia Rating (CDR) scores, were investigated using linear mixed models. We found significantly decreased synaptophysin and SV2A densities in the cortex of PD, PDD and DLB cases compared to controls. Specifically, synaptic density was decreased in cortical regions affected at Braak α-synuclein stage 5 in PD (middle temporal gyrus, anterior cingulate and insula), and was additionally decreased in cortical regions affected at Braak α-synuclein stage 4 in PDD and DLB compared to controls (entorhinal cortex, parahippocampal gyrus and fusiform gyrus). Synaptic loss associated with higher NfL immunoreactivity and LB density. Global synaptophysin loss associated with longer disease duration and higher CDR scores. Synaptic neurodegeneration occurred in temporal, cingulate and insular cortices in PD, as well as in parahippocampal regions in PDD and DLB. In addition, synaptic loss was linked to axonal damage and severe α-synuclein burden. These results, together with the association between synaptic loss and disease progression and cognitive impairment, indicate that regional synaptic loss may underlie clinical differences between PD and PDD/DLB. Our results might provide useful information for the interpretation of synaptic biomarkers in vivo.

This article discusses the case of a 31-year-old woman who presented with symptoms of headache, dizziness, and phosphenes. Magnetic resonance imaging (MRI) revealed a well-circumscribed mass in the left cerebellar hemisphere. The tumor was diagnosed as a cerebellar liponeurocytoma, a rare and slow-growing tumor that occurs in the cerebellum. The article highlights the diagnostic challenges of distinguishing cerebellar liponeurocytoma from other tumors, such as medulloblastoma, and emphasizes the importance of thorough examination and analysis of histological and immunohistochemical features for accurate diagnosis. The study concludes that cerebellar liponeurocytoma has distinct genetic and epigenetic features that can aid in diagnosis, and that the identification of lipomatous foci is crucial for distinguishing this tumor from other similar tumors. [Extracted from the article]

Background: Beneficial effects of whole-body vibration (WBV) on brain and musculoskeletal health in mice have been demonstrated, but underlying mechanisms remain relatively unrevealed. WBV improves attention and memory performance in mice, putatively through stimulation of the cholinergic system. Here, we investigated the effects of WBV on the septo-hippocampal cholinergic system. Methods: Young C57BL/6 mice (8 weeks old) were subjected to 10 min WBV/day (mechanical vibration: 30 Hz; ~0.1-μm peak-to-peak displacement), 5X/week for 5 weeks. In Experiment 1, choline acetyltransferase (ChAT)-immunoreactivity in the septum and hippocampus was analyzed either 2 or 24 h after the last WBV session. Pseudo-WBV-treated mice (same handling procedure as WBV, but no vibrations) served as controls. In Experiment 2, the longitudinal profile of ChAT-immunoreactivity was analyzed in the hippocampus after 1, 2, 3, 4, or 5 weeks of WBV. In addition, synaptophysin immunostaining was performed at either 2 and 5 weeks of WBV. Mice housed 1/cage during the entire experiment served as controls. The balance-beam test was used to monitor the functional impact of WBV. In Experiment 3, a Y-maze reference-memory test was performed after 5 weeks of WBV to obtain a functional cognitive outcome measure of WBV. Pseudo-WBV treated mice served as controls. Results: In Experiment 1, ChAT-immunoreactivity was significantly enhanced after the last WBV session of the 5-week period. This was found in the septum, Cornu Ammonis 1 (CA1), CA3, and dentate gyrus, and was dependent on layer and time-point (2 or 24 h). Experiment 2 revealed that, ChAT-immunoreactivity was lower after 2 weeks of WBV, whereas it was significantly higher after 5 weeks (similar to in Experiment 1). Immunostaining for synaptophysin, a marker for synaptic density, was also significantly higher after 5 weeks of WBV, but not significantly lower after 2 weeks, as was ChAT. WBV-treated groups performed significantly better than did controls on the balance beam from week 3 onwards. Experiment 3 showed that WBV-treated mice had better spatial-reference memory performance in the Y-maze test than did pseudo-WBV controls. Conclusions: Our results indicate that WBV stimulates the septo-hippocampal cholinergic system in a gradual and dynamic way that may contribute to improved spatial-memory performance. This finding suggests that WBV, by upregulation of the septo-hippocampal cholinergic system, may be considered a valuable therapeutic strategy to enhance brain functions in aging, neurodegenerative, and other brain diseases.