Expression Of Synaptophysin Research Articles

Evaluation of the neuroprotective effect of quercetin against damage caused by gamma radiation.

Radiation therapy is a routine clinical practice that has been used for a long time in the treatment of cancer patients. The most important dose-limiting organ in patients receiving radiotherapy for various conditions is the brain. The mechanisms underlying brain and pituitary gland damage caused by radiation are largely unknown. It is of great importance to use radioprotective agents to protect against damage. This study aims to evaluate the neuroprotective effects of quercetin in experimental radiation-induced brain and pituitary gland damage. A total of 60 adult male Wistar-albino rats were randomly divided into six groups (control, sham, radiation, quercetin, radiation + quercetin, and quercetin + radiation groups, with ten rats in each group). Quercetin was given to rats by oral gavage at 50 mg/kg/day. A whole-body single dose of 10 Gy radiation was applied to the rats. Tissue samples belonging to the groups were compared after excision. Histopathological changes in the brain tissue and pituitary gland were examined with hematoxylin-tissue samples in the groups and compared histologically and immunohistochemically. The histopathological examination of the brain and anterior pituitary gland sections showed marked damage in the radiation-treated rats, while the quercetin-administered groups showed normal tissue architecture. While neuropeptid Y immunoreactivity was increased, synaptophysin immunoreactivity was decreased in the brains of radiation-treated rats. However, when neuropeptide Y and synaptophysin expression were assessed in the anterior pituitary gland, there was no significant difference between the groups. Consequently, quercetin may be a potential pharmacological agent in modulating radiation-induced damage in rats. However, extra experimental and preclinical studies are needed to confirm our findings before they can be used clinically.

Pediatric-type high-grade neuroepithelial tumors with CIC gene fusion share a common DNA methylation signature

Pediatric neoplasms in the central nervous system (CNS) show extensive clinical and molecular heterogeneity and are fundamentally different from those occurring in adults. Molecular genetic testing contributes to accurate diagnosis and enables an optimal clinical management of affected children. Here, we investigated a rare, molecularly distinct type of pediatric high-grade neuroepithelial tumor (n = 18), that was identified through unsupervised visualization of genome-wide DNA methylation array data, together with copy number profiling, targeted next-generation DNA sequencing, and RNA transcriptome sequencing. DNA and/or RNA sequencing revealed recurrent fusions involving the capicua transcriptional repressor (CIC) gene in 10/10 tumor samples analyzed, with the most common fusion being CIC::LEUTX (n = 9). In addition, a CIC::NUTM1 fusion was detected in one of the tumors. Apart from the detected fusion events, no additional oncogenic alteration was identified in these tumors. The histopathological review demonstrated a morphologically heterogeneous group of high-grade neuroepithelial tumors with positive immunostaining for markers of glial differentiation in combination with weak and focal expression of synaptophysin, CD56 and CD99. All tumors were located in the supratentorial compartment, occurred during childhood (median age 8.5 years) and typically showed early relapses. In summary, we expand the spectrum of pediatric-type tumors of the CNS by reporting a previously uncharacterized group of rare high-grade neuroepithelial tumors that share a common DNA methylation signature and recurrent gene fusions involving the transcriptional repressor CIC. Downstream functional consequences of the fusion protein CIC::LEUTX and potential therapeutic implications need to be further investigated.

Ferulic acid improves cognitive impairment by regulating jumonji C domain-containing protein 6 and synaptophysin in the hippocampus in neonatal and juvenile rats with intrauterine hypoxia during pregnancy.

To investigate the impacts of ferulic acid (FA) on jumonji C domain-containing protein 6 (JMJD6) and synaptophysin in the tissues of the hippocampus in neonatal and juvenile rats with intrauterine hypoxia-induced cognitive impairment. The Sprague-Dawley pregnant rats were randomly divided into three groups: control, hypoxia, and hypoxia + FA. On day 14 of pregnancy, the intrauterine hypoxia model was created by placing pregnant rats in the hypoxic and low-pressure experimental chamber for 2 hr a day for 3 days. In the hypoxia + FA group, pregnant rats were injected intraperitoneally with 4% FA, once a day for 7 days. The hypoxia group was treated with equal amounts of saline. After delivery, JMJD6 and synaptophysin mRNA and proteins in the hippocampus regions were detected by in situ hybridization and western blotting. The Morris water maze was used to evaluate cognitive function. The neonatal and juvenile rats in the hypoxia group had significantly increased expression of JMJD6 and decreased expression of synaptophysin protein and synaptophysin I mRNA in the hippocampus than those in the control group. Meanwhile, hypoxia also clearly prolonged the escape latency and shortened the stay time in the target quadrant. FA decreased the expression of JMJD6 and increased the expression of synaptophysin and improved cognitive function compared with those in the hypoxia group. FA probably ameliorated the cognitive impairment by regulating JMJD6 and synaptophysin in the hippocampus of neonatal and juvenile rats who had intrauterine hypoxia during pregnancy.

The effect of experimentally-induced diabetes on rat hippocampus and the potential neuroprotective effect of Cerebrolysin combined with insulin. A histological and immunohistochemical study

ABSTRACT Diabetes Mellitus is the most common metabolic disorder affecting central nervous system (CNS) and is associated with altered brain structure. In this study, we assessed the ability of Cerebrolysin, alone and combined with insulin, to protect from the hippocampal degenerative changes in a diabetic rat model. Sixty adult male albino rats were equally divided into: control (gpI), diabetic (gpII), insulin-treated (gpIII), Cerebrolysin-treated (gpIV) and combined Insulin & Cerebrolysin-treated groups (gpV). Type-1 DM was induced by a single intraperitoneal injection of Streptozotocin (65 mg/kg) in groups (II, III, IV & V). Insulin was given subcutaneously (1 U/100g) daily, starting from the 4th day till the end of the experiment. Cerebrolysin was given intraperitonealy (5 ml/kg/day), starting from the 4th day till the end of the experiment. Hippocampus samples were collected 8-weeks post-injection. Hematoxylin & Eosin (H&E) and Immunohistochemical stains were used to assess the degenerative changes. The rat hippocampal region (CA3) and the dentate gyrus (DG) were subjected to microscopic examination and morphometric analysis. The hippocampus of rats of group II showed evident degenerative changes. Changes in immunohistochemical expression of Bax, TNF-alpha, Synaptophysin & GFAP were also detected. The morphometric study revealed changes in the thickness of layers and number of cells. Groups III and IV showed mild improvement in most parameters. Group V demonstrated marked improvement in most parameters and the hippocampus appeared more or less similar to the control. Cerebrolysin is a neurotropic drug that protects from the diabetic degenerative changes, especially if combined with insulin.

Intermittent Lead Exposure Induces Behavioral and Cardiovascular Alterations Associated with Neuroinflammation

The nervous system is the primary target for lead exposure and the developing brain appears to be especially susceptible, namely the hippocampus. The mechanisms of lead neurotoxicity remain unclear, but microgliosis and astrogliosis are potential candidates, leading to an inflammatory cascade and interrupting the pathways involved in hippocampal functions. Moreover, these molecular changes can be impactful as they may contribute to the pathophysiology of behavioral deficits and cardiovascular complications observed in chronic lead exposure. Nevertheless, the health effects and the underlying influence mechanism of intermittent lead exposure in the nervous and cardiovascular systems are still vague. Thus, we used a rat model of intermittent lead exposure to determine the systemic effects of lead and on microglial and astroglial activation in the hippocampal dentate gyrus throughout time. In this study, the intermittent group was exposed to lead from the fetal period until 12 weeks of age, no exposure (tap water) until 20 weeks, and a second exposure from 20 to 28 weeks of age. A control group (without lead exposure) matched in age and sex was used. At 12, 20 and 28 weeks of age, both groups were submitted to a physiological and behavioral evaluation. Behavioral tests were performed for the assessment of anxiety-like behavior and locomotor activity (open-field test), and memory (novel object recognition test). In the physiological evaluation, in an acute experiment, blood pressure, electrocardiogram, and heart and respiratory rates were recorded, and autonomic reflexes were evaluated. The expression of GFAP, Iba-1, NeuN and Synaptophysin in the hippocampal dentate gyrus was assessed. Intermittent lead exposure induced microgliosis and astrogliosis in the hippocampus of rats and changes in behavioral and cardiovascular function. We identified increases in GFAP and Iba1 markers together with presynaptic dysfunction in the hippocampus, concomitant with behavioral changes. This type of exposure produced significant long-term memory dysfunction. Regarding physiological changes, hypertension, tachypnea, baroreceptor reflex impairment and increased chemoreceptor reflex sensitivity were observed. In conclusion, the present study demonstrated the potential of lead intermittent exposure inducing reactive astrogliosis and microgliosis, along with a presynaptic loss that was accompanied by alterations of homeostatic mechanisms. This suggests that chronic neuroinflammation promoted by intermittent lead exposure since fetal period may increase the susceptibility to adverse events in individuals with pre-existing cardiovascular disease and/or in the elderly.

The dysfunctionality of hippocampal synapses may be directly related to PM-induced impairments in spatial learning and memory in juvenile rats

Epidemiological studies have demonstrated that exposure to air particulate matter (PM) increases the incidence of cardiovascular and respiratory diseases and exerts a significant neurotoxic effect on the nervous system, especially on the immature nervous system. Here, we selected PND28 rats to simulate the immature nervous system of young children and used neurobehavioral methods to examine how exposure to PM affected spatial learning and memory, as well as electrophysiology, molecular biology, and bioinformatics to study the morphology of hippocampus and the function of hippocampal synapses. We discovered that spatial learning and memory were impaired in rats exposed to PM. The morphology and structure of the hippocampus were altered in the PM group. In addition, after exposure to PM, the relative expression of synaptophysin (SYP) and postsynaptic density 95 (PSD95) proteins decreased dramatically in rats. Furthermore, PM exposure impaired long-term potentiation (LTP) in the hippocampal Schaffer-CA1 pathway. Interestingly, RNA sequencing and bioinformatics analysis revealed that the differentially expressed genes (DEGs) were rich in terms associated with synaptic function. Five hub genes (Agt, Camk2a, Grin2a, Snca, and Syngap1) that may play a significant role in the dysfunctionality of hippocampal synapses were identified.Our findings implied that exposure to PM impaired spatial learning and memory via exerting impacts on the dysfunctionality of hippocampal synapses in juvenile rats and that Agt, Camk2a, Grin2a, Snca, and Syngap1 may drive PM-caused synaptic dysfunction.

Selective Targeting of Class I HDAC Reduces Microglial Inflammation in the Entorhinal Cortex of Young APP/PS1 Mice.

BG45 is a class Ⅰ histone deacetylase inhibitor (HDACI) with selectivity for HDAC3. Our previous study demonstrated that BG45 can upregulate the expression of synaptic proteins and reduce the loss of neurons in the hippocampus of APPswe/PS1dE9 (APP/PS1) transgenic mice (Tg). The entorhinal cortex is a pivotal region that, along with the hippocampus, plays a critical role in memory in the Alzheimer's disease (AD) pathology process. In this study, we focused on the inflammatory changes in the entorhinal cortex of APP/PS1 mice and further explored the therapeutic effects of BG45 on the pathologies. The APP/PS1 mice were randomly divided into the transgenic group without BG45 (Tg group) and the BG45-treated groups. The BG45-treated groups were treated with BG45 at 2 months (2 m group), at 6 months (6 m group), or twice at 2 and 6 months (2 and 6 m group). The wild-type mice group (Wt group) served as the control. All mice were killed within 24 h after the last injection at 6 months. The results showed that amyloid-β (Aβ) deposition and IBA1-positive microglia and GFAP-positive astrocytes in the entorhinal cortex of the APP/PS1 mice progressively increased over time from 3 to 8 months of age. When the APP/PS1 mice were treated with BG45, the level of H3K9K14/H3 acetylation was improved and the expression of histonedeacetylase1, histonedeacetylase2, and histonedeacetylase3 was inhibited, especially in the 2 and 6 m group. BG45 alleviated Aβ deposition and reduced the phosphorylation level of tau protein. The number of IBA1-positive microglia and GFAP-positive astrocytes decreased with BG45 treatment, and the effect was more significant in the 2 and 6 m group. Meanwhile, the expression of synaptic proteins synaptophysin, postsynaptic density protein 95, and spinophilin was upregulated and the degeneration of neurons was alleviated. Moreover, BG45 reduced the gene expression of inflammatory cytokines interleukin-1β and tumor necrosis factor-α. Closely related to the CREB/BDNF/NF-kB pathway, the expression of p-CREB/CREB, BDNF, and TrkB was increased in all BG45 administered groups compared with the Tg group. However, the levels of p-NF-kB/NF-kB in the BG45 treatment groups were reduced. Therefore, we deduced that BG45 is a potential drug for AD by alleviating inflammation and regulating the CREB/BDNF/NF-kB pathway, and the early, repeated administration of BG45 can play a more effective role.

Moderate-Intensity Intermittent Training Alters the DNA Methylation Pattern of PDE4D Gene in Hippocampus to Improve the Ability of Spatial Learning and Memory in Aging Rats Reduced by D-Galactose

(1) Background: Aging is the main risk factor for most neurodegenerative diseases, and the inhibition of Phosphodiesterase 4(PDE4) is considered a potential target for the treatment of neurological diseases. The purpose of this study was to investigate the inhibitory effect of moderate-intensity intermittent training (MIIT) on PDE4 in the hippocampus of rats with D-galactose (D-gal)-induced cognitive impairment, and the possible mechanism of improving spatial learning and memory. (2) Methods: the aging rats were treated with D-Gal (150 mg/kg/day, for 6 weeks). The aging rats were treated with MIIT for exercise intervention (45 min/day, 5 days/week, for 8 weeks). The Morris water maze test was performed before and after MIIT to evaluate the spatial learning and memory ability, then to observe the synaptic ultrastructure of the hippocampus CA1 region, to detect the expression of synaptic-related protein synaptophysin (SYP) and postsynaptic density protein 95 (PSD95), and to detect the expression of PDE4 subtypes, cAMP, and its signal pathway protein kinase A (PKA)/cAMP response element binding protein (CREB)/brain-derived neurotrophic factor (BDNF), and the PDE4 methylation level. (3) Results: we found that MIIT for 8 weeks alleviated the decline in spatial learning and memory ability, and improved the synaptic structure of the hippocampus and the expression of synaptic protein SYP and PSD95 in D-Gal aging rats. To elucidate the mechanism of MIIT, we analyzed the expression of PDE4 isoforms PDE4A/PDE4B/PDE4D, cAMP, and the signaling pathway PKA/CREB/BDNF, which play an important role in memory consolidation and maintenance. The results showed that 8 weeks of MIIT significantly up-regulated cAMP, PKA, p-CREB, and BDNF protein expression, and down-regulated PDE4D mRNA and protein expression. Methylation analysis of the PDE4D gene showed that several CG sites in the promoter and exon1 regions were significantly up-regulated. (4) Conclusions: MIIT can improve the synaptic structure of the hippocampus CA1 area and improve the spatial learning and memory ability of aging rats, which may be related to the specific regulation of the PDE4D gene methylation level and inhibition of PDE4D expression.

The mitochondria-targeted small molecule SS31 delays progression of behavioral deficits by attenuating β-amyloid plaque formation and mitochondrial/synaptic deterioration in APP/PS1 mice

Alzheimer's disease (AD) is a common neurodegenerative disorder characterized by progressive cognitive dysfunction and an impaired ability to carry out daily life functions. Mitochondrial dysfunction and β-amyloid (Aβ) deposition are the most common causes of AD. Antioxidants have been shown to delay brain aging and AD development; however, it remains unknown whether the antioxidant peptide SS31 can protect mitochondrial and synaptic function and delay the progression of behavioral deficits in early-stage AD in vivo. Therefore, in this study we compared mitochondrial and synaptic changes, as well as the protective effects of SS31, in APP/PS1 transgenic mice and C57BL/6J control mice. The APP/PS1 transgenic mice exhibited elevated expression of Aβ40/Aβ42 and mitochondrial fission protein DLP1 and reduced expression of synaptophysin (SYN) and postsynaptic density protein 95 (PSD95) reductions, as well as increased levels of neuronal apoptosis and ROS in the hippocampus, and long-term treatment with SS31 reversed these effects. Furthermore, the cognitive impairments observed in APP/PS1 transgenic mice were reversed by SS31 treatment. Our findings show that SS31 lowers ROS and Aβ levels, protecting mitochondrial homeostasis and synaptic integrity, and ultimately improving behavioral deficits in early-stage AD. This suggests that SS31 is a potential pharmacological agent for treating or slowing the progression of AD.

Carcinoid-Like Cell Arrangements in Basal Cell Carcinoma: A Study of 11 Cases.

Background. Carcinoid-like pattern in basal cell carcinoma is extremely rare and has only been documented in a textbook. The aim of this study is to reveal the characteristics of the carcinoid-like pattern in basal cell carcinoma as well as to establish the concept of the tumor pattern. Methods. Of 355 basal cell carcinoma cases (355 lesions of 308 patients), 11 tumors with histopathological features of carcinoid-like pattern were retrieved. Results. The patients included 5 males and 6 females with a median age of 73 years (range 38-86 years). Of the 11 lesions, 10 were observed on the head. Histopathologically, a carcinoid-like pattern with branching and anastomosing of trabecular structures was observed in 30% to 95% of the tumor area. No differentiation to sebocytes was observed in any of the tumors. The tumors were well-circumscribed, although 3 lesions contained an infiltrative-type component as well. The carcinoid-like pattern areas in all 11 lesions exhibited diffuse BerEP4 immunoexpression but no KIT, synaptophysin, or vimentin expression. Keratin 20-positive Merkel cells were not observed in the tumor areas. Conclusions. Basal cell carcinoma can show a carcinoid-like pattern cell arrangement. Based on the histopathological and immunohistochemical findings from our study, we collectively conclude that the carcinoid-like pattern in basal cell carcinoma does not seem to represent sebaceous mantle differentiation. Carcinoid-like pattern basal cell carcinoma can be distinguished from other tumors by the favorite site of the head, the co-existence of conventional basal cell carcinoma components, lack of sebaceous differentiation, and diffuse BerEP4 immunoexpression.

Aerial part of Houttuynia cordata reverses memory impairment by regulating amyloid beta accumulation and neuroinflammation in Alzheimer's disease model.

Alzheimer's disease (AD) is the most common neurodegenerative disease characterized by amyloid-β (Aβ) deposition, accompanied by neuroinflammation and memory dysfunction. Houttuyniae Herba (aerial parts of Houttuynia cordata, also known as fish mint; HH), an herbal medicine traditionally used to treat fever, urinary disorders, and pus, is revealed to protect neurons from Aβ toxicity and regulate cholinergic dysfunction in AD models. In this study, we aimed to investigate the effects of HH on excessive accumulation of Aβ followed by neuroinflammation, synaptic degeneration, and memory impairment. Two-month-old 5xFAD transgenic mice were administered HH at 100 mg/kg for 4months. We observed that HH treatment ameliorated memory impairment and reduced Aβ deposits in the brains of the mice. HH directly inhibited Aβ aggregation in vitro using the Thioflavin T assay and indirectly suppressed the amyloidogenic pathway by increasing alpha-secretase expression in the mice brain. In addition, HH exerted antineuroinflammatory effects by reducing of glial activation and p38 phosphorylation. Moreover, HH treatment increased the expression of synaptophysin, a presynaptic marker protein. Overall, HH alleviates memory impairment in AD by facilitating nonamyloidogenic pathway and inhibiting neuroinflammation. Therefore, we suggest that HH can be a promising herbal drug for patients with AD requiring multifaceted improvement.

Association of emergent neuroendocrine prostate cancer detected by liquid biopsies with survival and treatment resistance.

247 Background: The mainstay of therapy in metastatic prostate cancer is androgen receptor (AR) signaling inhibition. However, the emergence of early castration resistance or neuroendocrine transformation is associated with poor prognosis. Reliable biomarkers are needed to identify these patients and guide selection of clinical therapy. Methods: mRNA was isolated from EpCAM-positive circulating tumor cells (CTCs) isolated from patients with CSPC, CRPC, or NEPC to measure expression of KLK2, KLK3 (PSA), TMPRSS2, FOLH1 (PSMA), synaptophysin ( SYP), and chromogranin ( CHGA). Post-hoc retrospective analysis of an institutional review board–approved prospective cohort (N = 98) was performed to identify patterns of gene expression. Samples were considered AR+ if 3 of 4 AR pathway genes ( TMPRSS2, KLK2, KLK3, and FOLH1) were positive, and were considered NE+ if either or both SYP or CHGA were positive. Blood samples from two prospective clinical trials of men with mCRPC treated with abiraterone and enzalutamide, respectively, were analyzed to confirm results. Longitudinal samples were collected from 17 patients (6 NEPC and 11 Adenocarcinoma) and cell free DNA was isolated and sequenced using a novel targeted exon panel. Results: AR and/or NE positive patients were found to have a median overall survival (OS) of 8.58 months as compared to a median OS of 29.6 months in the AR and NE negative population (p<0.0001; HR=2.75 [1.60-4.56]). In the subset of castrate resistant prostate cancer (CRPC) patients, AR+ and/or NE+ patients (n=31) were found to have a median OS of 6.74 months vs 18.79 months in the AR- and NE- group (n=39) (p= 0.0009; HR 2.38 [1.36-4.18]). We also tested samples from a phase II ARSI trials with abiraterone and enzalutamide, respectively. None of the baseline samples from these two trials met the above criteria for NEPC (AR- NE+) on their CTCs or histologically. Three of 48 total patients were identified with expression in their baseline blood samples without loss of AR target gene expression (AR+/NE+). Preliminary analysis of this small patient cohort in comparison to patients who were NE- shows that NE+ patients had worse OS (HR= 5.5906 [1.143-27.36), as would be expected by patients with emerging neuroendocrine differentiation. Integrated ctDNA sequencing identified mutations in genes associated with NEPC. Conclusions: The expression of NE genes in liquid biopsies while retaining AR target gene expression is associated with worse OS and may indicate the transition to neuroendocrine differentiation, with clinical characteristics consistent with this phenotype. Early identification of these patients may improve therapeutic decisions and improved patient outcomes. Pairing genomic alteration with changes in gene expression may additionally offer the basis for a new mechanism to assess efficacy of novel therapeutics in future clinical trials.

Ginsenoside ompound K reduces neuronal damage and improves neuronal synaptic dysfunction by targeting Aβ.

Background: Alzheimer's disease (AD) is the most common neurodegenerative condition worldwide, with amyloid ß (Aβ) fibrils presenting as its main pathological feature. This study investigated whether Ginsenoside Compound K (CK) has activity against Aβ and its mechanism in reducing synaptic damage and cognitive impairment. Methods: The binding capacity of CK to Aβ42 and Nrf2/Keap1 was determined using molecular docking. Transmission electron microscopy was used to monitor CK-mediated degradation of Aβ fibrils. The effect of CK on the survival of Aβ42-damaged HT22 cells was determined using a CCK-8 assay. The therapeutic efficacy of CK in a scopoletin hydrobromide (SCOP) induced cognitive dysfunction mouse model was measured using a step-down passive avoidance test. GO enrichment analysis of mouse brain tissue was peformed using Genechip. Hydroxyl radical scavenging and reactive oxygen species assays were performed to verify the antioxidant activity of CK. The effects of CK on the expression of Aβ42, the Nrf2/Keap1 signaling pathway, and other proteins were determined by western blotting, immunofluorescence, and immunohistochemistry. Results: Molecular docking results showed that CK interacts with Lys16 and Glu3 of Aβ42. CK reduced the aggregation of Aβ42 as observed using transmission electron microscopy. CK increased the level of insulin-degrading enzyme and decreased the levels ß-secretase and γ-secretase; therefore, it can potentially inhibit the accumulation of Aβ in neuronal extracellular space in vivo. CK improved cognitive impairment and increased postsynaptic density protein 95 and synaptophysin expression levels in mice with SCOP-induced cognitive dysfunction. Further, CK inhibited the expression of cytochrome C, Caspase-3, and cleaved Caspase-3. Based on Genechip data, CK was found to regulate molecular functions such as oxygen binding, peroxidase activity, hemoglobin binding, and oxidoreductase activity, thus affecting the production of oxidative free radicals in neurons. Further, CK regulated the expression of the Nrf2/Keap1 signaling pathway through its interaction with the Nrf2/Keap1 complex. Conclusion: Our findings show that CK regulates the balance between Aβ monomers production and clearance, CK binds to Aβ monomer to inhibits the accumulation of Aβ, increases the level of Nrf2 in neuronal nuclei, reduces oxidative damage of neurons, improves synaptic function, thus ultimately protecting neurons.

Clinical, pathologic, and molecular features of amphicrine prostate cancer.

Amphicrine prostate carcinoma (AMPC) is a poorly defined subset of prostate cancer in which cells co-express luminal prostate epithelial and neuroendocrine markers. The optimal treatment strategy is unknown. We sought to further characterize the clinical, histomorphologic, and molecular characteristics of AMPC and to identify areas of potential future treatment investigations. We retrospectively identified 17 cases of AMPC at a single institution, defined as synaptophysin expression in >70% of cells and co-expression of androgen receptor(AR) signaling markers (either AR, PSA, or NKX3.1) in >50% of cells. Clinical and histologic features of AMPC cases as well as response to treatment and clinical outcomes were described. Five AMPC cases arose de novo in the absence of prior systemic treatment and behaved distinctly from cases that were treatment-emergent. In these de novo cases, despite expression of neuroendocrine markers, prognosis appeared more favorable than high-grade neuroendocrine carcinoma, with two (40%) patients with de novo metastatic disease, universal response to androgen deprivation therapy, and no deaths at a median follow-up of 12.3 months. Treatment-emergent AMPC arose a median of 41.1 months after androgen deprivation therapy initiation and was associated with poor response to therapy. We show that amphicrine prostate cancer is a unique entity and differs in clinical and molecular features from high-grade neuroendocrine carcinomas of the prostate. Our study highlights the need to recognize AMPC as a unique molecularly defined subgroup of prostate cancer.

Maternal treatment with aripiprazole prevents the development of a valproic acid-induced autism-like phenotype in juvenile male mice.

Autism spectrum disorder (ASD) describes a heterogeneous group of neurodevelopmental conditions characterized by deficits in social communication and repetitive behaviors. Aripiprazole (APZ) is an atypical antipsychotic that can safeguard mice against autism-like behavior induced by valproic acid (VPA). In the present study, we examined the effects of maternal treatment with APZ (10 mg/kg) in juvenile mice prenatally exposed to VPA on neurodevelopmental behaviors, social interactions, communication, and working memory, as well as synaptophysin (SYP), synaptosomal-associated protein, 25 kDa (SNAP-25) and microtubule-associated protein 2 (MAP-2) expression in the medial prefrontal cortex (mPFC) and cell viability in the hippocampus. In addition, to evaluate possible APZ interference with the anticonvulsant properties of VPA on pentylenetetrazole (PTZ)-induced seizures were evaluated. Maternal treatment with APZ significantly prevented body weight loss, self-righting, eye-opening, social interactions, social communication, and working memory deficits in mice prenatally exposed to VPA. Additionally, the decrease in the SYP, SNAP-25, and MAP-2 expressions in the mPFC and cell death in the hippocampus was prevented by APZ. Furthermore, APZ (10 mg/kg) did not interfere with the anticonvulsant effect of VPA (15 mg/kg) in animals with PTZ-induced seizures. These findings indicate that maternal treatment with APZ in pregnant mice exposed to VPA protects animals against the ASD-like behavioral phenotype, and this effect may be related, at least in part, to synaptic plasticity and neuronal protection in the PFC and hippocampus. APZ may serve as an effective pharmacological therapeutic target against autistic behaviors in the VPA animal model of ASD, which should be further investigated to verify its clinical relevance.

The neuroprotective effect of ginsenoside Rb1 on the cerebral cortex changes induced by aluminium chloride in a mouse model of Alzheimer's disease: A histological, immunohistochemical, and biochemical study

Alzheimer's disease (AD) is one of the most common types of dementia among neurodegenerative disorders characterized by attention deficits and memory loss. Panax ginseng is a traditional Chinese herbal remedy that has been employed for millennia to manage dementia linked with aging and memory impairment. Ginsenoside Rb1 is one of Panax ginseng's most abundant components. The present work evaluated the neuroprotective effects of ginsenoside Rb1 on the cerebral cortex of AlCl3-induced AD in adult male albino mice. Forty male mice were alienated arbitrarily into; control group, ginsenoside Rb1 group (70 mg/kg/day), AlCl3 group (50 mg/kg/day), and ginsenoside Rb1-AlCl3 group that received ginsenoside Rb1 one hour before AlCl3. Oxidative stress parameters, Amyloid β (Aβ) and phosphorylated tau protein, and acetylcholine esterase (AChE) activity were measured. Cerebral cortex sections were evaluated histologically by light microscopic examination and immunohistochemistry. AlCl3-induced memory impairment, Aβ and phosphorylated tau protein accumulation, and AChE elevation. Moreover, histopathological alterations in the cerebral cortex were reported in the form of irregular shrunken neurons and the surrounding neuropil showed vacuolation. Some neurons appeared with darkly stained nuclei, others had faintly stained ones. The synaptophysin expression was significantly decreased, while the expression of cleaved caspase-3, glial fibrillary acidic protein (GFAP), and ionized calcium-binding adaptor molecule 1 (Iba-1) were significantly elevated. It's interesting to note that these changes were attenuated in mice pretreated with ginsenoside Rb1. Collected data indicated that ginsenoside Rb1 showed a potential neuroprotective effect against cerebral cortex changes caused by AlCl3 via suppression of Amyloid β and phosphorylated tau protein formation, oxidative stress correction, anti-apoptotic effect, and by minimizing gliosis.

Chlorpyrifos-induced dysregulation of synaptic plasticity in rat hippocampal neurons

Chlorpyrifos (CPF) is a widely used organophosphorus pesticide. Increasing evidence has shown that exposure to CPF in early life might induce neurodevelopmental disorders, but the pathogenesis remains uncertain. Synaptic plasticity plays a crucial role in neurodevelopment. This study aimed to investigate the effect of CPF on synaptic plasticity in hippocampal neurons and establish the cellular mechanism underlying these effects. Using CPF-exposed rat and primary hippocampal neurons model, we analyzed the impact of CPF on the synaptic morphology, the expression level of a presynaptic protein, a postsynaptic protein and ionotropic glutamate receptors (iGluRs), as well as the effects on the Wnt/β-catenin pathway. We found that the synapses were shortened, the spines were decreased, and the expression of synaptophysin (Syp), postsynaptic density-95 (PSD-95), GluN1, GluA1 and Wnt7a, as well as active β-catenin in primary hippocampal neurons was decreased. Our study suggests that CPF exposure induced dysregulation of synaptic plasticity in rat hippocampal neurons, which might provide novel information regarding the mechanism of CPF-induced neurodevelopmental disorders.

Dietary High-Fat Promotes Cognitive Impairment by Suppressing Mitophagy.

Dietary habits contribute to the characteristics of Alzheimer's disease (AD) and cognitive impairment, which are partly induced by the accumulation of hyperphosphorylated Tau, a microtubule-associated protein. In mice, a fat-rich diet facilitates cognitive dysfunction. However, the mechanism by which dietary fat damages the brain remains unclear. In this study, 13-month-old C57BL/6 mice were fed a normal or high-fat diet (HFD) for 6 months. Neuro-2a cells were incubated with the normal medium or palmitic acid (200 μM). Spatial memory was assessed utilizing a behavioral test. Further, western blotting and immunofluorescence techniques were used to determine the levels of mitophagy-related proteins. The synaptic morphology and phosphorylation of Tau proteins were also evaluated. Administration of HFD decreased the expression of synaptophysin and brain-derived neurotrophic factor expression, leading to significant damage to neurons. Tau protein hyperphosphorylation was detected at different loci both in vivo and in vitro. Significantly impaired learning and memory abilities, accompanied by impaired mitophagy-related processes, were observed in mice fed with HFD as compared to mice fed with normal food. In conclusion, high fatty-acid intake hinders mitophagy and upregulates Tau protein phosphorylation, including age-related synaptic dysfunction, which leads to cognitive decline.

Organoids of patient-derived medullary thyroid carcinoma: The first milestone towards a new in vitro model in dogs.

Organoid cultures could constitute a valuable in vitro model to explore new treatments for canine (c) medullary thyroid carcinoma (MTC). The study's objectives were to establish and characterize 3D organoid cultures of cMTC using histology and immunohistochemistry (IHC) and to evaluate the effect of antitumor drugs on organoids' viability. Five cMTC tissue samples were used to develop organoid cultures of which one organoid line, named cMTC N°2, could be passaged for an extended period. This cMTC N°2 organoid line was further compared to the primary tumour regarding morphology and IHC expression of thyroid transcription factor-1 (TTF-1), thyroglobulin, calcitonin, synaptophysin, vimentin, Ki-67, cyclooxygenase-2 (COX-2), P-glycoprotein and vascular endothelial growth factor (VEGF). Quality control of the cMTC N°2 organoid line was achieved by a single nucleotide polymorphism (SNP) array of the organoids, primary tumour and healthy blood cells of the same dog. The effect of carboplatin, meloxicam and toceranib phosphate (TOC) on cMTC N°2 organoids' viability was evaluated. The cMTC N°2 organoid line was cultured for 94 days and showed similar histological features with the primary tumour. Immunolabelling for TTF-1, thyroglobulin, calcitonin and VEGF was similar between the primary tumour and cMTC N°2 organoids. Compared to the primary tumour, organoids showed higher immunolabelling for vimentin and Ki-67, and lower immunolabelling for synaptophysin, COX-2 and P-glycoprotein. The SNP genotype was similar for each chromosome between healthy blood cells, primary tumour and cMTC N°2 organoids. Carboplatin, meloxicam and TOC had no effect on cMTC N°2 organoid cell viability within achievable in vivo concentration range. In conclusion, the cMTC N°2 organoid line is a promising first milestone towards an established in vitro organoid model to explore pathophysiology and new treatment modalities in cMTC.

Nerve growth factor causes epinephrine release dysfunction by regulating phenotype alterations and the function of adrenal medullary chromaffin cells in mice with allergic rhinitis.

The presence of allergic rhinitis (AR) is an increased risk factor for the occurrence of bronchial asthma (BA). Nerve growth factor (NGF), in addition to its key role in the development and differentiation of neurons, may also be an important inflammatory factor in AR and BA. However, the pathogenesis of the progression of AR to BA remains to be elucidated. The present study aimed to investigate the ability of NGF to mediate nasobronchial interactions and explore possible underlying molecular mechanisms. In the present study, an AR mouse model was established and histology of nasal mucosa tissue injury was determined. The level of phenylethanolamine N‑methyl transferase in adrenal medulla was determined by immunofluorescence. Primary adrenal medullary chromaffin cells (AMCCs) were isolated and cultured from the adrenal medulla of mice. The expression levels of synaptophysin (SYP), STAT1, JAK1, p38 and ERK in NGF‑treated and untreated AMCCs were detected by reverse‑transcription‑quantitative PCR and western blotting. The epinephrine (EPI) and norepinephrine (NE) concentrations were measured by ELISA. It was found that the expression of SYP in AMCCs was enhanced in the presence of NGF, whereas, the concentration of EPI decreased significantly under the same conditions. Furthermore, NGF mediated the phenotypic and functional changes of AMCCs, resulting in decreased EPI secretion via JAK1/STAT1, p38 and ERK signaling. In conclusion, these findings could provide novel evidence for the role of NGF in regulating neuroendocrine mechanisms.