Search Results (185)

Background/Objectives: Injuries to spinal ventral roots induce complex retrograde reactions that compromise motoneuron survival, synaptic organization, and glial responses, ultimately limiting the potential for regeneration. The endocannabinoid system (ECS) has emerged as a crucial modulator of neuroprotective processes, primarily through the activation of CB1 and CB2. However, the individual and combined contributions of these receptors to post-injury spinal responses remain poorly understood. Here, we examined the effects of selective blockade of CB1 and CB2 receptors in a murine model of ventral root crush (VRC). Methods: Female C57BL/6JUnib mice received daily intraperitoneal injections of the CB1 antagonist AM-251 and/or the CB2 antagonist AM-630 (1 mg/kg) for 14 days post-lesion. At 28 days after injury, spinal cords were analyzed for motoneuron survival (Nissl staining), glial responses (immunohistochemistry for GFAP and Iba-1), and synaptic coverage (immunohistochemistry for synaptophysin). Results: Selective blockade of CB2 receptors led to a marked reduction in motoneuron survival, enhanced microglial activation-associated morphology (morphological classification and Sholl analysis), and decreased synaptic coverage. CB1 blockade produced milder, context-dependent effects. Dual blockade exacerbated all outcomes, indicating complementary CB1/CB2 functions in the spinal microenvironment. Conclusions: Under the conditions tested, CB2 signaling is necessary for motoneuron preservation, limiting microglial activation-associated morphology, and maintaining synaptic coverage after VRC. The knowledge of specific actions of CB1 and CB2 provides mechanistic insight into the neuroprotective potential of endocannabinoid signaling and reinforces its therapeutic relevance for motoneuron preservation and functional recovery after axotomy. Full article

Background/Objectives: Astrocytic redox-inflammatory signaling has been implicated in Parkinson’s disease (PD) pathology and may constrain hippocampal neurogenesis. We previously identified an astrocytic NOX4–MPO–OPN axis associated with impaired neurogenic capacity. Here, we tested whether a saffron-derived antioxidant (SDA; Crocus sativus extract) and Passiflora incarnata L. extract (PI) modulate this pathway in an MPTP-induced PD mouse model. Methods: Male C57BL/6J mice were randomized to Sham, MPTP, and treatment groups (n = 9/group for behavior; n = 4–5/group for histology/immunoblotting). SDA or PI (50 mg/kg/day, oral, 5 weeks) was administered, with resveratrol as a positive control. Behavioral, histological, and molecular analyses were performed by investigators blinded to group allocation where feasible. Results: SDA and PI were associated with reduced NOX4/MPO/OPN signals, mainly in GFAP-positive astrocytes, along with recovery of neurogenesis markers (Ki67, DCX, BrdU/NeuN) and synaptic markers (PSD95, synaptophysin), and improved motor performance. Mitochondrial and oxidative injury markers (TIM23, TOM20, OXPHOS subunits; 4-HNE) and apoptotic markers (Bax, cleaved caspase-3, Bcl-2) also shifted toward Sham levels. Given previous reports of Passiflora extracts’ sedative effects, we note that metabolic measures (body weight, food intake, and water intake) were similar across groups; however, specific tests for sedation or arousal were not conducted. Conclusions: These findings offer preclinical evidence that SDA and PI modulate redox-inflammatory and mitochondrial stress signatures and are associated with neurogenic, synaptic, and behavioral improvements in an acute MPTP model. Further validation in chronic/genetic PD models and pharmacokinetic/brain exposure studies will be necessary to confirm their translational potential. Full article

Background/Objectives: Diabetic foot ulcers (DFUs) are one of the most debilitating complications of diabetes mellitus, characterized by impaired wound healing, chronic inflammation, and neuropathy. Peripheral nerve degeneration plays a critical role in delayed healing, but the molecular mediators linking hyperglycemia, neurodegeneration, and impaired DFU repair remain incompletely understood. This study aims to characterize the expression of activin A, which is a key regulator of fibroblast activity and neuronal growth, tumor necrosis factor receptor superfamily member 10B (TNFRSF10B), which mediates inflammatory and apoptotic signaling, and synaptophysin, which serves as a marker of axonal sprouting and synaptic remodeling in diabetic tissues. Methods: Skin tissues during wounding and after healing from control and diabetic Sprague–Dawley rats were analyzed using histological staining, immunohistochemistry, and quantitative real-time polymerase chain reactions. Additionally, rat fibroblasts were treated with hyperglycemic medium to evaluate gene and protein expression in vitro. Results: Histological analyses revealed impaired healing in diabetic wounds with reduced collagen deposition, loss of adnexal structures, and disorganized tissue architecture. Gene and protein expression of activin A, TNFRSF10B, and synaptophysin were significantly decreased in diabetic healed tissues compared to controls. In vitro, hyperglycemia induced transient upregulation of activin A and TNFRSF10B at 24 h, followed by a decline at 48 and 72 h. Conclusions: These findings indicate that hyperglycemia disrupts key mediators of axonal regeneration in DFUs, potentially contributing to impaired neuronal regeneration and delayed healing. Targeting these molecular pathways may offer therapeutic opportunities to enhance wound repair in DFUs. Full article

A 60-year-old woman with hypertension and hyperlipidemia was referred for an incidentally detected gastric subepithelial mass during screening endoscopy. Esophagogastroduodenoscopy revealed a 10 mm dimple in the antrum, and contrast-enhanced CT showed a 2.5 cm enhancing oval lesion. Laparoscopic partial gastrectomy with intraoperative endoscopic guidance was performed. Gross examination revealed a 3.0 × 2.0 × 1.0 cm pale, firm nodule. Histology showed small round cells arranged in nests and trabeculae within the muscularis propria, with numerous vessels and focal calcification. Immunohistochemistry was negative for CD117, HMB45, and chromogranin A, but demonstrated strong smooth muscle actin positivity, weak synaptophysin reactivity, and focal CD56 staining. The findings confirmed a gastric glomus tumor with neuroendocrine features. Smooth muscle actin immunostaining is essential to distinguish gastric glomus tumors from neuroendocrine tumors when biopsy material is limited, ensuring accurate diagnosis and appropriate management. Full article

Background: Large-cell carcinoma (LCC) and large-cell neuroendocrine carcinoma (LCNEC) are kinds of rare lung tumors classified as distinct forms of non-small-cell lung cancer (NSCLC). They both differ in cellular morphology, neuroendocrine marker expression, and clinical outcomes. Thus, LCC and LCNEC exhibit different clinicopathological characteristics and survival outcomes. This study seeks to assess how clinicopathological and immunohistochemical features influence the need for adjuvant chemotherapy in individuals with early-stage, surgically resected LCC or LCNEC. Methods: This multicenter retrospective analysis included 79 patients who underwent surgical resection for large-cell carcinoma (LCC) or large-cell neuroendocrine carcinoma (LCNEC) between January 2008 and March 2025. We evaluated prognostic factors that influence survival in patients with LCC and LCNEC and assessed the effect of adjuvant chemotherapy on survival outcomes. Results: This study included 79 patients—39 diagnosed with LCC and 40 diagnosed with LCNEC. All patients were in stages I–III and received curative surgery. The median age was 61 years for LCC patients and 58.5 years for LCNEC patients. The median overall survival (mOS) was 80.1 months for patients with LCC and 34.2 months for those with LCNEC. Multivariate Cox regression analysis revealed that age (HR: 0.279), stage (HR: 0.198), and chromogranin A expression (HR: 0.088) were independent prognostic factors for overall survival in LCC patients. In LCNEC patients, stage (HR: 0.20), synaptophysin expression (HR: 0.30), type of surgery (HR: 0.31), and adjuvant chemotherapy (HR: 0.264) were identified as factors influencing overall survival. Adjuvant chemotherapy improved overall survival in LCNEC patients (67.0 vs. 17.8 months). Conclusions: Patients with LCNEC generally have poorer prognoses than those with LCC, exhibiting reduced overall survival periods. Disease stage is the most significant factor influencing overall survival for both groups. Notably, in LCNEC patients, adjuvant chemotherapy was found to independently improve survival outcomes regardless of stage. Full article

Myocardial infarction (MI) and its sequelae continue to be the leading cause of mortality globally. Following MI, a series of structural pathophysiological changes occur in the myocardium, including sympathetic remodeling. Tyrosine hydroxylase (TH), protein gene product 9.5 (PGP9.5), and synaptophysin (SYN) are recognized as key markers of sympathetic nerves. However, the expression patterns of these biomarkers during sympathetic remodeling, particularly their temporal profiles, remain insufficiently characterized. A cohort of 60 healthy adult male C57BL/6 mice was randomly divided into a control group (n = 12) and four MI groups with postoperative intervals of 2, 5, 7, and 10 days (n = 12/group). MI was induced via permanent ligation of the left anterior descending coronary artery (LAD). Cardiac tissues were subjected to histological analyses (HE and Masson’s trichrome staining), immunohistochemical profiling, and quantitative reverse-transcriptase PCR (qRT-PCR) (TH, PGP9.5, and SYN). Immunohistochemical staining revealed that TH-, PGP9.5-, and SYN-immunopositive sympathetic nerves were present in the epicardium, myocardial interstitium, and the periphery of small blood vessels in normal mice. Normal cardiomyocytes were negative for TH but exhibited focal expression of PGP9.5 and SYN. In the myocardial infarction tissue, TH-positive staining indicated sympathetic nerve proliferation in the epicardium, myocardial infarction border zone, and infarct zone, with peak expression occurring at 7 days post-MI. In contrast to TH, PGP9.5 exhibited prominent immunoreactivity, specifically localized to the infarct core and peri-infarct zone cardiomyocytes, while SYN was primarily located in fibroblast-like cells within the same region. qRT-PCR analyses revealed that the time-dependent trends of TH, PGP9.5, and SYN mRNAs exhibited similarities, peaking between 5 and 7 days post-MI. TH demonstrates higher specificity than PGP9.5 and SYN in sympathetic nerve identification, solidifying its role as the optimal biomarker for post-MI sympathetic remodeling. The ectopic expression of PGP9.5 and SYN in non-neuronal cells within myocardial infarction tissue remains speculative and requires further mechanistic studies for validation. Full article

Multiple differentiation protocols have emerged in recent years, producing neurons with diverse morphologies, gene and protein expression profiles, and functionality. Many of these differentiation techniques require months of culture and the use of expensive growth factors. Most importantly, the derived neurons usually do not exhibit any electrical activity. This limits the value of the protocol as a tool for engineering and investigating neural networks. Here, we describe an efficacious method for differentiating mouse embryonic stem cells into functional neurons. CGR8 cells were neurally induced via the simultaneous application of retinoic acid and purmorphamine. The derived cells expressed neuronal (TUJ1 and NeuN) and synaptic (GAD2, PSD-95, Synaptophysin, and VGLUT1) markers. During whole-cell recordings, neurons exhibited inward and outward currents, likely caused by fast-inactivating voltage-gated potassium channels. Upon current injection, miniature action potentials were also recorded. The efficient generation of diverse subtypes of functional neurons can be a useful tool in fundamental investigations of neural network activity and translational studies. Full article

Using the fly eye as a model system, we previously demonstrated that upregulation of the fly gene mask protects against FUS- and Tau-induced photoreceptor degeneration. Building upon this finding, we investigated whether the protective role of mask is conserved in mammals. To this end, we generated a transgenic mouse line carrying Cre-inducible ANKHD1, the human homolog of mask. Utilizing the TauP301S-PS19 mouse model for Tau-related dementia, we found that expressing ANKHD1 driven by CamK2a-Cre reduced hyperphosphorylated human Tau in 6-month-old mice. Additionally, ANKHD1 expression was associated with a trend toward reduced gliosis and preservation of the presynaptic marker Synaptophysin, suggesting a protective role of ANKHD1 against TauP301S-linked neuropathology. At 9 months of age, novel object recognition (NOR) testing revealed cognitive impairment in female, but not male, PS19 mice. Notably, co-expression of ANKHD1 restored cognitive performance in the affected female mice. Together, this study highlights the novel effect of ANKHD1 in counteracting the adverse effects induced by the mutant human Tau protein. This finding underscores ANKHD1’s potential as a unique therapeutic target for tauopathies. Full article

As the size of the elderly population increases, the need for an improved understanding of what leads to the age-related decline in physiological function continues to grow. SAMP8 mice were selected for their accelerated aging phenotype. The low levels of glyoxalase 1 (Glo1), the main enzyme that removes the reactive dicarbonyl methylglyoxal (MGO), in the cerebral cortex of SAMP8 mice prompted us to produce the first transgenic mice overexpressing Glo1 against the SAMP8 background, aimed at rescuing the accelerated aging phenotype. Selected health and biochemical endpoints were assessed in ten-month-old SAMP8 mice overexpressing Glo1. Glo1 overexpression increased median survival in males (21%) and females (4.6%), which was associated with better memory performance. Glo1 overexpression also increased synaptic markers (synaptophysin and SNAP25) as well as markers of mitochondrial function (NDUFB8, SDHB) and negative modulators of oxytosis/ferroptosis (NQO1, FTH1, and GPx4) in the cerebral cortex. For all parameters analyzed, the effect of Glo1 overexpression was more pronounced in males. Overall, the data support the beneficial effects of overexpressing Glo1 in multiple tissues, especially in SAMP8 males, suggesting a possible gender effect of MGO in aging. Both modulation of oxytosis/ferroptosis and mitochondrial metabolism warrant further investigation as potential mechanisms underlying the improved health span of Glo1 mice. Full article

Background/Objectives: Contextual memory associated with methamphetamine (METH) use contributes to relapse and persistence of addiction. Angiotensin II type 1 receptor (AT1R) signaling has been implicated in drug reinforcement. LCZ696, a clinically used combination of sacubitril (a neprilysin inhibitor) and valsartan (an AT1R antagonist), may interfere with METH-associated memory through the modulation of dopaminergic pathways. Methods: Male C57BL/6J mice were tested in a conditioned place preference (CPP) paradigm to assess the effects of LCZ696, sacubitril (AHU377), and valsartan on METH-induced memory expression and reinstatement. Synaptic plasticity in the nucleus accumbens (NAc) was examined by assessing the levels of synaptophysin (Syp) and postsynaptic density protein 95 (Psd95), as well as dendritic spine density. Dopaminergic signaling in the ventral tegmental area (VTA) was evaluated via ELISA, Western blotting, and chromatin immunoprecipitation (ChIP), targeting cAMP response element-binding protein (Creb) binding to the tyrosine hydroxylase (Th) promoter. To further assess the role of Th, an adeno-associated virus (AAV9) carrying a CRISPR-Cas9-based sgRNA targeting Th (AAV9-Th-sgRNA) was microinjected into the VTA. Results: LCZ696 and valsartan significantly reduced METH-induced CPP and reinstatement. LCZ696 reversed METH-induced synaptic and dopaminergic alterations and suppressed Creb-mediated Th transcription. Th knockdown attenuated both CPP acquisition and relapse. Conclusions: LCZ696 disrupts METH-associated contextual memory by modulating dopaminergic signaling and Creb-dependent Th expression, supporting its potential as a treatment for METH use disorder. Full article

Background: Elevated levels of methylmalonic acid (MMA) are observed in the bodily fluids and tissues of patients with methylmalonic aciduria, a metabolic disorder characterized by manifestations such as vomiting, lethargy, muscle weakness, seizures, and coma. Objectives and Methods: To better understand the neuropathological mechanisms underlying this condition, we investigated the effects of intraperitoneal (i.p.) and intracerebroventricular (i.c.v.) administration of MMA on antioxidant defenses, citric acid cycle functioning, and glial reactivity in the cerebral cortex and striatum of Wistar rats. Amino acid levels were also quantified. Results: i.p. and i.c.v. administration of MMA decreased reduced glutathione levels and altered the activities of different antioxidant enzymes in the cortex and striatum. The activity of the citric acid cycle enzyme succinate dehydrogenase was diminished in both brain regions by i.p. and i.c.v. administration. Citrate synthase, isocitrate dehydrogenase, and malate dehydrogenase activities were further inhibited in the striatum. Furthermore, the i.p. administration increased glial fibrillary acidic protein (GFAP) and glucose transporter 1 (GLUT1) levels, whereas i.c.v. administration elevated GFAP and ionized calcium-binding adaptor molecule 1 (IBA1) levels in the striatum, suggesting glial activation. In contrast, no significant changes in glial markers were detected in the cortex. Moreover, synaptophysin levels remained unaltered in both regions. Finally, i.p. administration increased glutamate, glycine, and serine levels and reduced tyrosine concentrations in the striatum. Conclusions: Our findings indicate that oxidative stress, bioenergetic dysfunction, and glial reactivity induced by MMA may contribute to the neurological deficits observed in methylmalonic aciduria. Full article

Background: The role and underlying mechanisms of synaptophysin-like-1 (SYPL1), a neuroendocrine-associated protein, in pancreatic ductal adenocarcinoma (PDAC) remain unclear. This study aims to assess the diagnostic potential of SYPL1 as a serum biomarker for both resectable PDAC (rPDAC) and metastatic PDAC (mPDAC) located at the head of the pancreas. Additionally, the SYPL1 levels were monitored in PDAC patients who underwent surgical resection, with follow-up measurements taken 6 months postoperatively. Method: We analyzed serum SYPL1 in healthy controls (n = 67), rPDAC patients (n = 39), mPDAC patients (n = 22), and rPDAC patients (6-month postoperative) (n = 20) (due to factors such as relocation or death, 20 patients were included instead of 39 patients) by ELISA. Results: The SYPL-1 levels showed significant differences across the groups (controls: 7.43 ± 3.32, PC: 15.89 ± 2.00, mPDAC: 20.01 ± 4.03, p < 0.001). Both carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) were significantly greater in cancer groups compared to the healthy group. In patients who underwent surgical resection, the SYPL-1 levels showed a significant decrease 6 months after surgery (p < 0.001). Strong correlations were observed between tumor markers, with CA19-9 showing a positive correlation with CEA in both rPDAC (r = 0.550, p < 0.001) and mPDAC (r = 0.623, p = 0.002), while SYPL-1 demonstrated a negative correlation with CEA (r = −0.530, p = 0.009) in mPDAC. Receiver operating characteristic (ROC) analysis revealed excellent diagnostic performance for SYPL-1 in distinguishing both rPDAC (AUC = 0.965) and mPDAC (AUC = 0.985) from healthy controls, achieving superior accuracy compared to conventional markers CEA and CA19-9. Conclusions: Serum SYPL-1 emerges as a promising biomarker for the diagnosis and monitoring of rPDAC and mPDAC. Its significantly elevated levels in cancer groups, coupled with its marked decrease following surgical resection, suggest that SYPL-1 could play a critical role in both initial diagnosis and post-treatment surveillance. The strong correlations observed between SYPL-1, CEA, and CA19-9 further support its potential utility in a multi-marker panel. Notably, SYPL-1 demonstrated superior diagnostic accuracy compared to conventional markers, with high AUC values indicating its excellent ability to distinguish rPDAC and mPDAC from healthy controls. These findings highlight the need for further investigation to validate SYPL-1 as a reliable, non-invasive biomarker that could enhance early detection, prognosis, and treatment monitoring in rPDAC. Full article

As the average age of the population increases, memory impairment has become an increasingly prevalent issue. This study investigates the effects of 14 days of oral birch sap administration on memory functions in healthy rats using the Morris water maze (MWM) test and explores the underlying mechanisms. A compositional analysis revealed that birch soap is rich in polysaccharides, specifically a low-molecular weight polysaccharide (MW 1.29 kDa), and exhibits no hepatotoxicity or renal toxicity at the tested dose. The results from the MWM test demonstrated that the time and distance required to reach the platform were significantly shorter in the birch sap-treated group compared to the control group, suggesting that birch sap supports memory preservation. Moreover, rats treated with birch sap showed improved cerebral blood flow compared to the control rats. Additionally, in hippocampal nerve terminals (synaptosomes), rats treated with birch sap exhibited a significant increase in evoked glutamate release, as well as elevated levels of presynaptic proteins, including vesicular glutamate transporter 1 (VGluT1), synaptophysin, synaptobrevin, synaptotagmin, syntaxin, synapsin I, and the 25 kDa synaptosome-associated protein (SNAP-25). Transmission electron microscopy also revealed a notable increase in the number of synaptic vesicles in hippocampal synaptosomes of the birch-sap-treated rats. These findings suggest that birch sap enhances hippocampal presynaptic glutamatergic functions and cerebral blood flow, contributing to its memory-preserving effects in rats. Full article

Strumal carcinoid tumors of the ovary are rare neoplasms composed of an intimate mixture of thyroid and carcinoid tissues. Although various theories regarding their histogenesis have been proposed, evidence confirming the origin of the carcinoid component has been lacking. We report a case of a 40-year-old female with an ovarian strumal carcinoid arising in the background of a mature cystic teratoma. Morphological and immunohistochemical findings support the hypothesis that the carcinoid component originates from the thyroid follicular epithelium, undergoing neuroendocrine differentiation. A single-cell growth pattern was also identified, expanding the known histological spectrum of strumal carcinoids. Our case provides additional immunohistochemical support for the histogenetic origin of strumal carcinoids, offering new insights into their pathogenesis. Recognizing these distinct patterns of staining and unusual morphology is critical for accurate diagnosis and differentiation from metastatic disease. Full article

Background: Sleep deprivation (SD) is a common condition affecting many people in modern life. Edaravone (Eda) is a neuroprotective drug, but whether it can improve cognitive impairment caused by SD remains unclear. Methods: Animals received oral gavage doses of Eda (10, 20, and 40 mg/kg) for 8 and 5 days before and during SD. Starting from the 6th day, a modified multiple platform model was used to produce SD in mice for 72 h. The Lashley III maze was used for evaluating spatial learning and memory. Malondialdehyde (MDA) in the hippocampus and serum corticosterone were assessed. Total antioxidant capacity (TAC) and the activity of the enzymes glutathione peroxidase (GPx) and superoxide dismutase (SOD) were measured. Growth-associated protein 43 (GAP-43), synapsin 1 (SYN-1), post-synaptic density-95 (PSD-95), synaptophysin (SYP), and signs of inflammation were detected using Western blotting. Results: SD caused cognitive impairment, whereas Eda pretreatment warded off such an effect. While serum corticosterone levels rose with SD as well, they decreased in SD mice that received Eda (p < 0.05). Moreover, Eda normalized the SD-induced decline in hippocampal activity of SOD and GPx, lowered MDA levels, and elevated TAC (p < 0.01). Additionally, the hippocampal levels of GAP-34, SYP, SYN-I, and PSD-95 were elevated, while IL-1β and tumor necrosis factor α (TNF-α) were lowered following Eda pretreatment (p < 0.05). Conclusions: SD caused memory impairment; however, pretreatment with Eda improved memory by upregulating synaptic proteins in the hippocampus and having anti-inflammatory and antioxidant effects. Full article