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Cells Jun 2024Methyl-CpG-binding protein 2 () is an epigenetic modulator and numerous studies have explored its impact on the central nervous system manifestations. However, little...
Methyl-CpG-binding protein 2 () is an epigenetic modulator and numerous studies have explored its impact on the central nervous system manifestations. However, little attention has been given to its potential contributions to the peripheral nervous system (PNS). To investigate the regulation of in the PNS on specific central regions, we generated mice with the sensory-neuron-specific deletion of the gene and found the mutant mice had a heightened sensitivity to temperature, which, however, did not affect the sense of motion, social behaviors, and anxiety-like behavior. Notably, in comparison to mice, mice exhibited improved learning and memory abilities. The levels of hippocampal synaptophysin and PSD95 proteins were higher in mice than in mice. Golgi staining revealed a significant increase in total spine density, and dendritic arborization in the hippocampal pyramidal neurons of mice compared to mice. In addition, the activation of the BDNF-TrkB-CREB1 pathway was observed in the hippocampus and spinal cord of mice. Intriguingly, the hippocampal BDNF/CREB1 signaling pathway in mutant mice was initiated within 5 days after birth. Our findings suggest a potential therapeutic strategy targeting the BDNF-TrkB-CREB1 signaling pathway and peripheral somasensory neurons to treat learning and cognitive deficits associated with Mecp2 disorders.
Topics: Animals; Methyl-CpG-Binding Protein 2; Hippocampus; Dendritic Spines; Mice; Cognition; Brain-Derived Neurotrophic Factor; Sensory Receptor Cells; Cyclic AMP Response Element-Binding Protein; Male; Signal Transduction; Mice, Inbred C57BL; Receptor, trkB
PubMed: 38891120
DOI: 10.3390/cells13110988 -
Cells May 2024Apolipoprotein E (ApoE) is a lipid carrier in both the peripheral and the central nervous systems (CNSs). Lipid-loaded ApoE lipoprotein particles bind to several cell...
Apolipoprotein E (ApoE) is a lipid carrier in both the peripheral and the central nervous systems (CNSs). Lipid-loaded ApoE lipoprotein particles bind to several cell surface receptors to support membrane homeostasis and brain injury repair. In the brain, ApoE is produced predominantly by astrocytes, but it is also abundantly expressed in most neurons of the CNS. In this study, we addressed the role of ApoE in the hippocampus in mice, focusing on its role in response to radiation injury. To this aim, 8-week-old, wild-type, and ApoE-deficient (ApoE) female mice were acutely whole-body irradiated with 3 Gy of X-rays (0.89 Gy/min), then sacrificed 150 days post-irradiation. In addition, age-matching ApoE females were chronically whole-body irradiated (20 mGy/d, cumulative dose of 3 Gy) for 150 days at the low dose-rate facility at the Institute of Environmental Sciences (IES), Rokkasho, Japan. To seek for ApoE-dependent modification during lineage progression from neural stem cells to neurons, we have evaluated the cellular composition of the dentate gyrus in unexposed and irradiated mice using stage-specific markers of adult neurogenesis. Our findings indicate that ApoE genetic inactivation markedly perturbs adult hippocampal neurogenesis in unexposed and irradiated mice. The effect of ApoE inactivation on the expression of a panel of miRNAs with an established role in hippocampal neurogenesis, as well as its transcriptional consequences in their target genes regulating neurogenic program, have also been analyzed. Our data show that the absence of ApoE also influences synaptic functionality and integration by interfering with the regulation of mir-34a, mir-29b, and mir-128b, leading to the downregulation of synaptic markers PSD95 and synaptophysin mRNA. Finally, compared to acute irradiation, chronic exposure of ApoE null mice yields fewer consequences except for the increased microglia-mediated neuroinflammation. Exploring the function of ApoE in the hippocampus could have implications for developing therapeutic approaches to alleviate radiation-induced brain injury.
Topics: Animals; Apolipoproteins E; Hippocampus; Mice; Radiation, Ionizing; Female; MicroRNAs; Mice, Inbred C57BL; Neurons; Neurogenesis; Whole-Body Irradiation; Radiation Exposure; Dentate Gyrus
PubMed: 38891031
DOI: 10.3390/cells13110899 -
International Journal of Surgery Case... Jul 2024Cystic lesions in the retrorectal space include developmental abnormality, inflammatory process, and tumor-relevant cysts. Among them, the tailgut cyst is the most...
INTRODUCTION AND IMPORTANCE
Cystic lesions in the retrorectal space include developmental abnormality, inflammatory process, and tumor-relevant cysts. Among them, the tailgut cyst is the most common lesion which is featured by the complex epithelium lining the wall. It is generally accepted that tailgut cysts are embryonic residues and are mostly benign, but there are also reports about malignant transformation and even metastasis.
CASE PRESENTATION
A 44-year-old female complained a sacrococcygeal discomfort more than one year. The imaging diagnosis was an infectious cyst. After surgery, a solid region was defined in a cyst. Morphologically, the region was composed of bland epithelia forming glandular or ribbon-like structure, with round nuclei and fine chromatin. Immunohistochemically, the cells were positive for CK7, CD56 and synaptophysin. The Ki-67-positive cells were about 1 %. The final diagnosis is a low-grade neuroendocrine tumor arising in a tailgut cyst. The patient was living without recurrence by the follow-up of 20 months after surgery.
CLINICAL DISCUSSION
By reviewing the previously reported NET arising from tailgut cysts, we summarized 29 cases of neuroendocrine neoplasms that reported detailed information, and the majority are women. We found that the higher-grade tumor presented a higher tendency of distant metastasis or recurrence after surgery. Complete resection and full evaluation by pathologists are necessary to get a correct diagnosis and avoid disease progression.
CONCLUSION
We reported the rare case of NET G1 arising from a tailgut cyst and reviewed relevant reports, in order to broaden differential diagnoses when an isolated mass is identified in the retrorectal space.
PubMed: 38889516
DOI: 10.1016/j.ijscr.2024.109912 -
Archives of Pathology & Laboratory... Jun 2024Insulinoma-associated protein-1 (INSM1) is a recently developed immunohistochemical marker claimed to be highly specific and sensitive for the diagnosis of...
CONTEXT.—
Insulinoma-associated protein-1 (INSM1) is a recently developed immunohistochemical marker claimed to be highly specific and sensitive for the diagnosis of neuroendocrine malignancies. Recent studies, however, have demonstrated that this marker can also be expressed in non-neuroendocrine neoplasms including squamous cell carcinoma of the thymus.
OBJECTIVE.—
To examine INSM1 expression in lymphoepithelial thymic carcinomas.
DESIGN.—
Thirty-four cases of lymphoepithelial carcinoma of the thymus were examined by immunohistochemistry or in situ hybridization for INSM1, synaptophysin, chromogranin, CD5, CD117, Epstein-Barr virus-encoded small ribonucleic acid (EBER), and Ki-67. Basic clinical information was abstracted from the medical record.
RESULTS.—
The patients were 14 women and 20 men, aged 20 to 85 years. The tumors arose in the anterior mediastinum without any previous history or evidence of malignancy at other sites. Immunohistochemical staining showed moderate to strong positivity of the tumor cells for INSM1 in 65% of cases (22 of 34), focal weak positivity in 20% (7 of 34), and negative staining in 5 cases. Chromogranin staining was focally and weakly positive in 1 case, and synaptophysin showed only focal weak positivity in scattered tumor cells in 12 cases. No significant correlation could be identified between the pattern and intensity of staining for INSM1 and staining for CD5, CD117, and Ki-67.
CONCLUSIONS.—
INSM1 positivity in lymphoepithelial carcinoma of the thymus may represent a pitfall for diagnosis, particularly in small biopsy samples. Awareness of this finding may be of importance to avoid misdiagnosis of neuroendocrine malignancy.
PubMed: 38884541
DOI: 10.5858/arpa.2024-0045-OA -
Frontiers in Oncology 2024Cases of mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) of the urinary system are rare, and reports of primary MiNENs in the ureter are lacking. Herein, we...
Cases of mixed neuroendocrine-non-neuroendocrine neoplasms (MiNENs) of the urinary system are rare, and reports of primary MiNENs in the ureter are lacking. Herein, we present the case of a 71-year-old man who presented with painless gross hematuria and weight loss. Contrast-enhanced abdominal computed tomography (CT) revealed a tumor, comprising small cell neuroendocrine carcinoma (SCNEC) and adenocarcinomatous components, attached to the ureter. The SCNEC components were strongly positive for synaptophysin, CD56 and INSM1 and adenocarcinomatous components were strongly positive for CDX2 and cytokeratin 20, respectively. Four weeks post-surgery, the patient received four cycles of cisplatin-based chemotherapy; the 7-month follow-up CT confirmed that he was healthy without disease recurrence. The occurrence of MiNEN in the ureter with SCNEC and adenocarcinomatous components is extremely rare, wherein histopathological and immunohistochemical features aid in the diagnosis MiNEN. With its aggressive nature, MiNEN can only be effectively treated by early diagnosis and radical surgery.
PubMed: 38884082
DOI: 10.3389/fonc.2024.1390350 -
Annals of Diagnostic Pathology Jun 2024Five cases of thoracic solitary fibrous tumor (SFT) with small cell features are presented mimicking a neuroendocrine neoplasm. The patients were four men and one woman...
Five cases of thoracic solitary fibrous tumor (SFT) with small cell features are presented mimicking a neuroendocrine neoplasm. The patients were four men and one woman aged 43 to 74 years who presented with symptoms of chest pain, cough, dyspnea or hemoptysis. Two tumors were intrapulmonary neoplasms, while three were pleural-based. Grossly, the tumors ranged in size from 4 to 6 cm and were white and solid; in two tumors necrosis was apparent. Histologically, they were characterized by a cellular proliferation composed of small cells with round nuclei and inconspicuous nucleoli. The cellular proliferation in some areas had a subtle nested pattern, while in other areas the tumor showed extensive sclerosis and small vessel proliferation. Cellular pleomorphism was not marked and the mitotic activity varied from 1 to 5 mitotic figures per 10 high power fields. Microscopically, necrosis was observed in two cases and focally present in one. Immunohistochemical stains showed tumors cells universally negative for pancytokeratin; in the two pulmonary cases, focal staining for synaptophysin, CD56, and INSM1 was observed. The unexpected lack of expression of pancytokeratin led to additional analysis revealing positive staining with CD34 and STAT6 confirming a diagnosis of SFT. Clinical follow-up showed tumor recurrence in one patient while three patients remained alive and well after a period of 12 to 20 months. The current cases highlight an unusual variant of SFT that may be confused with other small cell tumor entities, such as neuroendocrine or neuroectodermal tumors, especially when originating in the thoracic cavity.
PubMed: 38878688
DOI: 10.1016/j.anndiagpath.2024.152353 -
Pathology Oncology Research : POR 2024Gastric epithelial neoplasm of the fundic-gland mucosa lineages (GEN-FGMLs) are rare forms of gastric tumors that encompass oxyntic gland adenoma (OGA), gastric...
BACKGROUND
Gastric epithelial neoplasm of the fundic-gland mucosa lineages (GEN-FGMLs) are rare forms of gastric tumors that encompass oxyntic gland adenoma (OGA), gastric adenocarcinoma of the fundic-gland type (GA-FG), and gastric adenocarcinoma of the fundic-gland mucosa type (GA-FGM). There is no consensus on the cause, classification, and clinicopathological features of GEN-FGMLs, and misdiagnosis is common because of similarities in symptoms.
METHODS
37 cases diagnosed with GEN-FGMLs were included in this study. H&E-stained slides were reviewed and clinicopathological parameters were recorded. Immunohistochemical staining was conducted for MUC2, MUC5AC, MUC6, CD10, CD56, synaptophysin, chromograninA, p53, Ki67, pepsinogen-I, H/K-ATPase and Desmin.
RESULTS
The patients' ages ranged from 42 to 79 years, with a median age of 60. 17 were male and 20 were female. Morphologically, 19 OGAs, 16 GA-FGs, and two GA-FGMs were identified. Histopathological similarities exist between OGA, GA-FG, and GA-FGM. The tumors demonstrated well-formed glands, expanding with dense growth patterns comprising pale, blue-grey columnar cells with mild nuclear atypia. These cells resembled fundic gland cells. None of the OGA invaded the submucosal layer. The normal gastric pit epithelium covered the entire surface of the OGA and GA-FG, but the dysplasia pit epithelium covered the GA-FGM. Non-atrophic gastritis was observed in more than half of the background mucosa. All cases were diffusely positive for MUC6 and pepsinogen-I on immunohistochemistry. H/K-ATPase staining was negative or showed a scattered pattern in most cases. MUC5AC was expressed on the surface of GA-FGMs. p53 was focally expressed and the Ki67 index was low (1%-20%). Compared with OGA, GA-FG and GA-FGM were more prominent in the macroscopic view ( < 0.05) and had larger sizes ( < 0.0001). Additionally, GA-FG and GA-FGM exhibited higher Ki67 indices than OGA ( < 0.0001). Specimens with Ki-67 proliferation indices >2.5% and size >4.5 mm are more likely to be diagnosed with GA-FG and GA-FGM than OGA.
CONCLUSION
GEN-FGMLs are group of well-differentiated gastric tumors with favourable biological behaviours, low cellular atypia, and low proliferation. Immunohistochemistry is critical for confirming diagnosis. Compared with OGA, GA-FG and GA-FGM have larger sizes and higher Ki67 proliferation indices, indicating that they play a critical role in the identification of GEN-FGML. Pathologists and endoscopists should be cautious to prevent misdiagnosis and overtreatment, especially in biopsy specimens.
Topics: Humans; Stomach Neoplasms; Male; Female; Middle Aged; Aged; Adult; Ki-67 Antigen; Gastric Mucosa; Biomarkers, Tumor; Adenocarcinoma; Gastric Fundus; Adenoma; Prognosis
PubMed: 38873175
DOI: 10.3389/pore.2024.1611734 -
FASEB Journal : Official Publication of... Jun 2024Subclinical hypothyroidism (SCH) in pregnancy is the most common form of thyroid dysfunction in pregnancy, which can affect fetal nervous system development and increase...
Subclinical hypothyroidism (SCH) in pregnancy is the most common form of thyroid dysfunction in pregnancy, which can affect fetal nervous system development and increase the risk of neurodevelopmental disorders after birth. However, the mechanism of the effect of maternal subclinical hypothyroidism on fetal brain development and behavioral phenotypes is still unclear and requires further study. In this study, we constructed a mouse model of maternal subclinical hypothyroidism by exposing dams to drinking water containing 50 ppm propylthiouracil (PTU) during pregnancy and found that its offspring were accompanied by severe cognitive deficits by behavioral testing. Mechanistically, gestational SCH resulted in the upregulation of protein expression and activity of HDAC1/2/3 in the hippocampus of the offspring. ChIP analysis revealed that H3K9ac on the neurogranin (Ng) promoter was reduced in the hippocampus of the offspring of SCH, with a significant reduction in Ng protein, leading to reduced expression levels of synaptic plasticity markers PSD95 (a membrane-associated protein in the postsynaptic density) and SYN (synaptophysin, a specific marker for presynaptic terminals), and impaired synaptic plasticity. In addition, administration of MS-275 (an HDAC1/2/3-specific inhibitor) to SCH offspring alleviated impaired synaptic plasticity and cognitive dysfunction in offspring. Thus, our study suggests that maternal subclinical hypothyroidism may mediate offspring cognitive dysfunction through the HDAC1/2/3-H3K9ac-Ng pathway. Our study contributes to the understanding of the signaling mechanisms underlying maternal subclinical hypothyroidism-mediated cognitive impairment in the offspring.
Topics: Animals; Neurogranin; Hypothyroidism; Female; Pregnancy; Mice; Cognitive Dysfunction; Histone Deacetylase 2; Prenatal Exposure Delayed Effects; Histone Deacetylase 1; Down-Regulation; Hippocampus; Male; Histone Deacetylases; Mice, Inbred C57BL; Neuronal Plasticity
PubMed: 38865202
DOI: 10.1096/fj.202400389R -
Clinical Journal of Gastroenterology Jun 2024Although gastric neuroendocrine tumors (NETs) are uncommon compared with gastric carcinomas, the incidence of NETs has been recently increasing. Gastric NETs are...
Although gastric neuroendocrine tumors (NETs) are uncommon compared with gastric carcinomas, the incidence of NETs has been recently increasing. Gastric NETs are classified into three subgroups, and among these, gastrin-independent sporadic type 3 gastric NETs have a poor prognosis because of frequent lymph node or distant metastasis. We experienced a case of an early-stage type 3 gastric NET associated with lymphovascular and submucosal invasion. In a 54 year-old woman, esophagogastroduodenoscopy performed during a health screening identified an elevated lesion of the upper body of the stomach. The results of immunohistochemical analyses of endoscopic biopsy specimens obtained from the lesion were positive for chromogranin A and synaptophysin, indicating an NET. Because the patient's serum gastrin level was normal and she had no predisposing conditions for NET development, the tumor was diagnosed as a type 3 gastric NET. The patient underwent local resection of the tumor and regional lymph node dissection. The resected specimen indicated a diagnosis of type 3 gastric NET with invasion into the submucosa and lymphatic duct. This is an extremely rare case of an early-stage type 3 gastric NET. Our discussion provides insight into the pathogenesis and development of these tumors and the appropriate therapeutic strategy.
PubMed: 38865017
DOI: 10.1007/s12328-024-01999-8 -
Cell Death Discovery Jun 2024Heat exposure is an environmental stressor that has been associated with cognitive impairment. However, the neural mechanisms that underlie this phenomenon have yet to...
Heat exposure is an environmental stressor that has been associated with cognitive impairment. However, the neural mechanisms that underlie this phenomenon have yet to be extensively investigated. The Morris water maze test was utilized to assess cognitive performance. RNA sequencing was employed to discover the primary regulators and pathological pathways involved in cognitive impairment caused by heat. Before heat exposure in vivo and in vitro, activation of the sarco/endoplasmic reticulum (SR/ER) calcium (Ca)-ATPase (SERCA) was achieved by CDN1163. Hematoxylin-Eosin, Nissl staining, calcium imaging, transmission electron microscopy, western blot, and immunofluorescence were utilized to visualize histological changes, intracellular calcium levels, endoplasmic reticulum stress (ERS) markers, apoptosis, and synaptic proteins alterations. Heat stress (HS) significantly induced cognitive decline and neuronal damage in mice. By the transcriptome sequencing between control (n = 5) and heat stress (n = 5) mice in hippocampal tissues, we identified a reduction in the expression of the atp2a gene encoding SERCA, accompanied by a corresponding decrease in its protein level. Consequently, this dysregulation resulted in an excessive accumulation of intracellular calcium ions. Furthermore, HS exposure also activated ERS and apoptosis, as evidenced by the upregulation of p-PERK, p-eIF2α, CHOP, and caspase-3. Consistently, a reduction in postsynaptic density protein 95 (PSD95) and synaptophysin (SYN) expressions indicated modifications in synaptic function. Notably, the impacts on neurons caused by HS were found to be mitigated by CDN1163 treatment both in vivo and in vitro. Additionally, SERCA-mediated ERS-induced apoptosis was attenuated by GSK2606414 treatment via inhibiting PERK-eIF2α-CHOP axis that not only curtailed the level of caspase-3 but also elevated the levels of PSD95 and SYN. These findings highlight the significant impact of heat stress on cognitive impairment, and further elucidate the underlying mechanism involving SERCA/PERK/eIF2α pathway.
PubMed: 38862478
DOI: 10.1038/s41420-024-02047-7