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Journal of Ethnopharmacology Jun 2024The traditional medicinal formulation, Qifu-yin (QFY), has been widely prescribed for Alzheimer's disease (AD) treatment in China, yet the comprehensive mechanisms...
ETHNOPHARMACOLOGICAL RELEVANCE
The traditional medicinal formulation, Qifu-yin (QFY), has been widely prescribed for Alzheimer's disease (AD) treatment in China, yet the comprehensive mechanisms through which QFY mitigates AD pathology remain to be fully delineated.
AIM OF THE STUDY
This study aimed to explore the therapeutic implications of QFY on the synaptic injury and oxidative stress in the hippocampus of APPswe/PS1dE9 (APP/PS1) mice, with a concerted effort to elucidate the molecular mechanisms related to synaptic preservation and memory improvement.
MATERIALS AND METHODS
The components of QFY were identified by ultra-high-performance liquid chromatography-tandem mass spectrometry (UHPLC-MS/MS). The neuroprotective effects of QFY was evaluated using six-month-old male APP/PS1 mice. Subsequent to a 15 days of QFY regimen, spatial memory was assessed utilizing the Morris water maze (MWM) test. Amyloid-beta (Aβ) aggregation was detected via immunostaining, while the quantification of Aβ and Aβ was achieved through enzyme-linked immunosorbent assay (ELISA). Transmission electron microscopy (TEM) was used to investigate the synaptic structure and mitochondrial morphology. Golgi staining was applied to examine dendritic spine density. Reactive oxygen species (ROS), 3-nitrotyrosine (3-NT) and 4-hydroxy-nonenal (4-HNE) assays were employed to assess oxidative stress. The expression profiles of Aβ metabolism-associated enzymes and the Keap1/Nrf2/ARE signaling pathway were determined by Western blot.
RESULTS
A total of 20 principal compounds in QFY were identified. QFY mitigated memory deficits of APP/PS1 mice, including reducing escape latency and search distance and increasing the time and distance spent in the target quadrant. In addition, QFY increased platform crossings of APP/PS1 mice in the probe trial of MWM tests. TEM analysis showed that QFY increased synapse number in the CA1 region of APP/PS1 mice. Further studies indicated that QFY elevated the expression levels of Post synaptic density protein 95 (PSD95) and synaptophysin, and mitigated the loss of dendritic spine density in the hippocampus of APP/PS1 mice. QFY has been shown to ameliorated the structural abnormalities of mitochondria, including mitochondrial dissolution and degradation, up-regulate ATP synthesis and membrane potential in the hippocampus of APP/PS1 mice. Moreover, QFY activated the Keap1/Nrf2/ARE signaling pathway in the hippocampus of APP/PS1 mice, which might contribute to the neuroprotective effects of QFY.
CONCLUSION
QFY activates the Keap1/Nrf2/ARE signaling, and protects against synaptic and mitochondrial dysfunction in APP/PS1 mice, proposing a potential alternative therapeutic strategy for AD management.
PubMed: 38942156
DOI: 10.1016/j.jep.2024.118497 -
Metallomics : Integrated Biometal... Jun 2024Ferric-tannic nanoparticles (FTs) are now considered to be new pharmaceuticals appropriate for the prevention of brain aging and related diseases. We have previously...
Ferric-tannic nanoparticles (FTs) are now considered to be new pharmaceuticals appropriate for the prevention of brain aging and related diseases. We have previously shown that FTs could activate axon guidance pathways and cellular clearance functioning in neuronal cell lines. Herein, we further investigated whether FTs could activate the two coordinated neuronal functions of axon guidance and synaptic function in rat brains and neuronal cell lines. A single intravenous injection of safe dose of FTs has been shown to activate a protein expression of axon attractant Netrin-1 and neurotransmitter receptor GABRA4 in the cerebral cortexes of male Wistar rats. According to RNA-seq with targeted analysis, axon guidance and synapses have been enriched and Ephrin membered genes have been identified as coordinating a network of genes for such processes. In vitro, as expected, FTs are also found to activate axon guidance markers and promote neuronal tubes in neuronal cell lines. At the same time, presynaptic markers (synaptophysin), post-synaptic markers (synapsin), and GABRA4 neurotransmitter receptors have been found to be activated by FTs. Interestingly, synaptophysin has been found to localize along the promoted neuronal tubes, suggesting that enhanced axon guidance is associated with the formation and transportation of pre-synaptic vesicles. Preliminarily, repeated injection of FTs into adult rats every 3 days for 10 times could enhance an expression of synaptophysin in cerebral cortex, as compared to control rat. This work demonstrates that FTs can be used for activating brain function associated with axon guidance and synaptic function.
PubMed: 38936837
DOI: 10.1093/mtomcs/mfae031 -
Journal of Diabetes and Metabolic... Jun 2024Defective insulin signaling in the brain may disrupt hippocampal neuroplasticity resulting in learning and memory impairments. Thus, this study investigated the effect...
Aerobic exercise training improves memory function through modulation of brain-derived neurotrophic factor and synaptic proteins in the hippocampus and prefrontal cortex of type 2 diabetic rats.
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.
PubMed: 38932906
DOI: 10.1007/s40200-023-01360-9 -
Cancer Biology & Therapy Dec 2024Prostate cancer has heterogeneous growth patterns, and its prognosis is the poorest when it progresses to a neuroendocrine phenotype. Using bioinformatic analysis, we...
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.
Topics: Humans; Male; Prostatic Neoplasms; Adenocarcinoma; Biomarkers, Tumor; Gene Expression Regulation, Neoplastic; Synaptophysin; Extracellular Vesicles; Gene Expression Profiling
PubMed: 38926911
DOI: 10.1080/15384047.2024.2364433 -
Acta Neuropathologica Communications Jun 2024A novel histomolecular tumor of the central nervous system (CNS), the "diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters (DGONC)," has...
Diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters (DGONC), new name and new problems: an illustration of one case with atypical morphology and biology.
A novel histomolecular tumor of the central nervous system (CNS), the "diffuse glioneuronal tumor with oligodendroglioma-like features and nuclear clusters (DGONC)," has recently been identified, based on a distinct DNA methylation profile and has been added to the 2021 World Health Organization Classification of CNS Tumors. This glioneuronal tumor mainly affects the supratentorial area in children and recurrently presents with a monosomy of chromosome 14. Herein, we report the case of a DNA-methylation based diagnosis of DGONC having atypical features, such as pseudo-rosettes and the absence of a chromosome 14 monosomy, thus rendering its diagnosis very challenging. Because of the wide variety of morphologies harbored by DGONC, a large range of differential diagnoses may be hypothesized from benign to malignant. Interestingly, the current case, like one previously reported, exhibited a co-expression of OLIG2, synaptophysin and SOX10, without GFAP immunopositivity. This particular immunophenotype seems to be a good indicator for a DGONC diagnosis. The classification of DGONC amongst glioneuronal or embryonal tumors is still debated. The clinical (a pediatric supratentorial tumor), morphological (from a benign oligodendroglioma-like tumor with microcalcifications and possible neuropil-like islands to a malignant embryonal tumor with a possible spongioblastic pattern), and immunohistochemical (co-expression of OLIG2 and synaptophsyin) profiles resemble CNS, neuroblastoma, FOXR2-activated and may potentially bring them together in a future classification. Further comprehensive studies are needed to conclude the cellular origin of DGONC and its prognosis.
Topics: Child; Humans; Brain Neoplasms; DNA Methylation; Oligodendroglioma
PubMed: 38926880
DOI: 10.1186/s40478-024-01822-y -
Biomedicine & Pharmacotherapy =... Jun 2024There is a lack of a systematic understanding of the specific mechanism of action of DL0410 in AD treatment. In this study, the combination of RNA-seq and proteomics was...
There is a lack of a systematic understanding of the specific mechanism of action of DL0410 in AD treatment. In this study, the combination of RNA-seq and proteomics was firstly employed to uncover the mechanism of action of DL0410 in APP/PS1 transgenic mice. The results of behavioral tests showed that oral administration of DL0410 for 8 weeks improved memory and cognition of APP/PS1 mice. DL0410 significantly reduced β-amyloid deposition and resulted in significant upregulation of synaptophysin, PSD95 and NMDAR/ CaMKⅡ signaling pathway in the hippocampus and cortex, indicating that DL0410 improved synaptic plasticity in APP/PS1 mice, which agrees with the results of RNA-seq and proteomics. Furthermore, the enrichment results of differentially expressed genes identified by RNA-seq and proteomics demonstrate the potential protective effects of DL0410 against oxidative stress and mitochondrial dysfunction. As expected, DL0410 dose-dependently ameliorated oxidative damage and markedly increased the expression of PGC-1α, TFAM, SOD1 and SOD2. Mitochondrial high-resolution respirometry results revealed that mitochondrial respiratory function was significantly improved in APP/PS1 mice administered with DL0410. In addition, DL0410 treatment reduced oxidative damage, strengthened antioxidant system and improved mitochondrial function in Aβ-induced HT22 cells. Altogether, our findings suggest the potential of DL0410 as a novel candidate for AD treatment.
PubMed: 38925020
DOI: 10.1016/j.biopha.2024.116940 -
International Journal of Surgery Case... Jun 2024Large cell neuroendocrine carcinomas of the colon (LCNECC) are exceptionally rare, comprising only 0.2 % of all colonic carcinomas. Their diagnosis poses a significant...
INTRODUCTION AND IMPORTANCE
Large cell neuroendocrine carcinomas of the colon (LCNECC) are exceptionally rare, comprising only 0.2 % of all colonic carcinomas. Their diagnosis poses a significant challenge due to their propensity to mimic colonic adenocarcinomas. Typically diagnosed at advanced stages, LCNECCs carry a grim prognosis. Herein, we present a rare case of LCNECC and aim to elucidate its clinico-pathological characteristics.
CASE PRESENTATION
A 56-year-old female patient presented with complaints of constipation, abdominal pain, and weight loss. On physical examination, a sizable mass was palpable in the right flank. Colonoscopy revealed a polyp in the descending colon and a friable multinodular stenosing mass in the ascending colon. Microscopic examination of the biopsy from the ascending colon mass exhibited a poorly differentiated large cell carcinomatous proliferation with positivity for synaptophysin and CD56, along with a Ki-67 proliferation index of 50 %. The polyp in the descending colon was consistent with a low-grade dysplastic tubular adenoma. A diagnosis of LCNECC with synchronous low-grade dysplastic tubular adenoma was established. A right hemicoloctomy was performed. Final pathological examination confirmed LCNECC invading the muscularis propria, with lymph node metastases. The tumor was classified as pT2N1M0 (Stage III).
CLINICAL DISCUSSION
LCNECCs often mimic adenocarcinomas clinically, endoscopically, and radiologically. Pathological examination is the key for diagnosis. An immunohistochemical study using neuroendocrine markers is imperative to prevent overlooking the diagnosis of LCNECC.
CONCLUSION
LCNECCs represent rare aggressive carcinomas. Their diagnosis might be challenging. A better knowledge of this rare entities would enable early diagnosis.
PubMed: 38917703
DOI: 10.1016/j.ijscr.2024.109929 -
Journal of Neuropathology and... Jun 2024Mixed pituitary adenoma/PitNET-gangliocytomas (PA/PitNET-GC) have been reported in small series over the past 20 years; some had limited immunohistochemistry (IHC)...
Mixed pituitary adenoma/PitNET-gangliocytomas (PA/PitNET-GC) have been reported in small series over the past 20 years; some had limited immunohistochemistry (IHC) data. We interrogated our experience over 20 years, focusing on patterns of the GC component and IHC results for anterior pituitary hormones, transcription factors, NFP, and CAM5.2. A search of cases from 2002 to 2023 yielded 20 cases: 7M:13F, ages 20-71 years; 17 macroadenomas, 1 microadenoma, 2 ectopic. GC was co-associated with 4 corticotroph, 2 densely granulated lactotroph, 5 mixed lactotroph-somatotroph, 1 immature PIT1-lineage tumor, and 8 sparsely granulated GH; the latter all had a minor lactotroph component. Patterns were: discrete nodular foci of GC (9/20), extensive GC differentiation often overshadowing the PA/PitNET (7/20), and intimate admixture of smaller bands of neuropil and individual metaplastic ganglion cells within PA/PitNET (4/20). NFP highlighted small cohesive regions of neuropil and identified greater axonal content, including individual axons within "pure" PA/PitNET areas, than appreciated on H&E. CAM5.2 IHC often revealed cells with neuronal morphologies to a greater extent than NFP and in different areas within the same tumor. These data suggest that the combined use of NFP and CAM5.2 IHC best reveals transition from PA to GC phenotype, with CAM5.2 positivity reflecting earlier stages of transformation.
PubMed: 38917431
DOI: 10.1093/jnen/nlae050 -
Cureus May 2024Central neurocytoma (CN) is a rare, low-grade, neuronal tumor frequently encountered in young adults. Complete surgical resection is the treatment of choice; however, it...
Central neurocytoma (CN) is a rare, low-grade, neuronal tumor frequently encountered in young adults. Complete surgical resection is the treatment of choice; however, it is associated with grave postoperative complications in a quarter of patients, including neurological (motor weakness, memory deficit, aphasia, and seizure) as well as regional (hydrocephalus, hematoma, infection, and subcutaneous hydrops) complications. Herein, we present a case of a 35-year-old female who presented with decreased vision for the last 7-8 days and headache over the last 1-1.5 years. An ophthalmologic examination suggested papilledema. Magnetic resonance imaging (MRI) of the brain illustrated a well-circumscribed, large, lobulated, altered signal intensity midline intraventricular lesion (72 × 68 mm) attached to the septum pellucidum near the foramen of Monro (FoM) most likely to be CN. The patient underwent complete surgical resection but required re-exploration the next day for hematoma removal due to intraventricular hemorrhage. Over the next 40 days, the patient developed hydrocephalus with transtentorial herniation and succumbed. Histopathological examination (HPE) was suggestive of CN and immunohistochemistry (IHC) was strongly positive for synaptophysin, thus confirming the diagnosis of CN.
PubMed: 38915980
DOI: 10.7759/cureus.60969 -
Biochimica Et Biophysica Acta.... Jun 2024The regulation of protein degradation through the ubiquitin-proteasome system is essential for normal brain development, axon growth, synaptic growth and plasticity. The...
The regulation of protein degradation through the ubiquitin-proteasome system is essential for normal brain development, axon growth, synaptic growth and plasticity. The E3 ubiquitin ligase RFWD2 plays a key role in the onset and development of neurological diseases, including the pathogenesis of Alzheimer's disease (AD), but the mechanisms controlling the homeostasis of neuronal synaptic proteins are still poorly understood. Here, we showed that the expression level of RFWD2 gradually decreased with the age of the rats and was negatively correlated with the development of cerebral cortical neurons and dendrites in vivo. RFWD2 was shown to localize to presynaptic terminals and some postsynaptic sides of both excitatory synapses and inhibitory synapses via colocalization with neuronal synaptic proteins (SYN, PSD95, Vglut1 and GAD67). Overexpression of RFWD2 promoted dendrite development and dendritic spine formation and markedly decreased the expression of synaptophysin and PSD95 by reducing the expression of ETV1, ETV4, ETV5 and c-JUN in vitro. Furthermore, the whole-cell membrane slice clamp results showed that RFWD2 overexpression resulted in greater membrane capacitance in neuronal cells, inadequate cell repolarization, and a longer time course for neurons to emit action potentials with decreased excitability. RFWD2 regulates dendritic development and plasticity, dendritic spine formation and synaptic function in rat cerebral cortex neurons by activating the ERK/PEA3/c-Jun pathway via a posttranslational regulatory mechanism and can be used as an efficient treatment target for neurological diseases.
PubMed: 38909848
DOI: 10.1016/j.bbadis.2024.167319