Maintaining telomere integrity is essential for cellular survival, and reactivation of telomerase or alternative lengthening of telomeres (ALT) represents a hallmark of cancer, ensuring replicative immortality. Osteosarcoma (OS), a malignancy in which many tumors rely on ALT for telomere maintenance, lacks effective therapeutic strategies targeting this pathway. This study aimed to identify and characterize novel molecular regulators of ALT activity and explore their potential as therapeutic targets in OS. Methods: Immunohistochemistry was performed to evaluate the expression of phosphorylated NPM1 (pT199-NPM1) in OS tissues. Functional experiments including NPM1 knockdown and rescue assays were conducted to assess the impact of NPM1 on break-induced telomere replication (BITR) and cell viability in ALT-positive cells. Mechanistic studies involving phosphorylation analysis, ubiquitination assays, and co-immunoprecipitation were used to determine how ATR-mediated phosphorylation of NPM1 regulates POLD3 stability and its interaction with the CST complex. Pharmacological screening was performed to identify compounds that inhibit ALT activity, followed by in vitro proliferation assays and in vivo mouse xenograft experiments to evaluate therapeutic efficacy and synergy with doxorubicin. Results: We identified pT199-NPM1 as a novel, highly expressed protein factor in ALT-positive OS tissues. NPM1 depletion impaired break-induced telomere replication and significantly reduced the viability of ALT-positive cells. ATR signaling phosphorylated NPM1 at Thr199, which stabilized POLD3 by preventing its ubiquitin-mediated degradation. Recruitment and function of pT199-NPM1 at telomeric damage sites required STN1, defining a CST/pT199-NPM1/POLD3 regulatory axis essential for ALT activity. Clinically, elevated Thr199 phosphorylation correlated with poor survival in OS patients, while expression of a phosphorylation-deficient T199A mutant failed to sustain ALT telomere maintenance. Pharmacological screening identified EPZ-6438, an EZH2 inhibitor, as a potent ALT suppressor that reduced NPM1 transcription, inhibited homologous recombination-mediated telomere synthesis, and suppressed OS cell proliferation. In mouse xenografts, EPZ-6438 enhanced OS cell sensitivity to doxorubicin, suggesting therapeutic synergy. Conclusions: This study uncovers a novel CST/pT199-NPM1/POLD3 regulatory module that is critical for ALT telomere maintenance in OS. Targeting NPM1 or its downstream effectors effectively suppresses ALT activity and enhances chemotherapy response. These findings provide new mechanistic insights into telomere regulation in ALT-positive tumors and highlight the therapeutic potential of NPM1-centered pathways in OS.

Background:Glioma remains a challenging malignancy with limited therapeutic options, and the underlying molecular mechanisms driving its progression are not fully understood. Although miR-506-5p has been implicated in various tumors, its role in glioma progression and the associated mechanisms warrant further investigation. This study aims to explore whether miR-506-5p suppresses glioma growth and invasion by targeting MAPK7, thereby regulating matrix metalloproteinases (MMPs) and epithelial-mesenchymal transition (EMT). Methods:Expression levels of miR-506-5p and MAPK7 in glioma tissues and cell lines were examined by reverse transcription quantitative polymerase chain reaction (RT-qPCR). The direct interaction between miR-506-5p and MAPK7 was validated using dual-luciferase reporter assays. Gain- and loss-of-function approaches were employed in U87 glioma cells, followed by 5-ethynyl-2'-deoxyuridine (EdU), wound healing, and Transwell assays to assess proliferation, migration, and invasion. Western blotting was performed to evaluate MAPK7, MMPs, and EMT-related markers. Rescue experiments were conducted to confirm the involvement of MAPK7 in miR-506-5p-mediated effects. Additionally, a xenograft model was established to evaluate the anti-tumor activity of miR-506-5p in vivo. Results:MiR-506-5p expression was significantly downregulated, while MAPK7 expression was markedly upregulated, in glioma tissues and cell lines compared with controls. Dual-luciferase reporter assays confirmed that miR-506-5p directly targeted the 3'-UTR of MAPK7. Overexpression of miR-506-5p suppressed cell proliferation, migration, invasion, and EMT, accompanied by decreased expression of MAPK7, MMP9, MMP12, N-cadherin, and vimentin, and increased E-cadherin expression. Conversely, miR-506-5p knockdown produced opposite effects. Rescue experiments demonstrated that MAPK7 overexpression reversed the suppressive effects induced by miR-506-5p, whereas MAPK7 knockdown reversed the pro-tumorigenic effects of miR-506-5p inhibition. In vivo, miR-506-5p overexpression significantly inhibited xenograft tumor growth, reduced Ki-67 positivity, and recapitulated the molecular changes observed in vitro. Conclusions:MiR-506-5p functions as a tumor suppressor in glioma by directly targeting MAPK7, thereby inhibiting MMP expression and EMT to suppress tumor growth, migration, and invasion. The miR-506-5p/MAPK7 axis represents a potential therapeutic target for glioma intervention.

BACKGROUND:The abuse of methamphetamine (METH) is associated with an increased risk of Parkinson's disease (PD), whereas microglial polarization and glucose metabolism disorders are closely related to the progression of PD. This study aimed to investigate the specific molecular mechanism underlying the promotion of PD progression by METH through the regulation of microglial polarization and glycolysis. METHODS:METH-induced C57BL/6 mice and BV2 cells were used to construct PD-like neurotoxicity animal and cell models for experimental investigation. Behavioral tests, immunohistochemistry and Nissl staining were used to assess the behavioral ability and neuronal damage of the animals. The levels of related proteins, inflammatory cytokines and glycolysis were detected using immunofluorescence, ELISA, Western blotting, and CCK-8 assays. RESULTS:METH treatment significantly promoted behavioral disorders in PD mice, reduced the number of TH-positive neurons, and aggravated neuronal damage in the substantia nigra (SN). In addition, METH decreased the M2 marker proteins Arg-1 and CD206 and increased the M1 marker proteins iNOS and CD86; the proinflammatory cytokines TNF-α, IL-β, and IL-6; and glucose uptake, glucose consumption and lactic acid production, thus promoting M1 polarization and glycolytic activity in BV2 cells. In terms of the underlying molecular mechanism, METH treatment significantly increased the level of LPA. METH promotes LPA expression via upregulation of LIPH expression, and activates the PI3K/AKT pathway. Knockdown of LIPH or treatment with BrP-LPA reduces the ability of METH to promote M1 microglial polarization and glycolytic activity. Furthermore, the addition of the PI3K/AKT signaling pathway activator 740 YP weakened the inhibitory effect of BrP-LPA on the above process. CONCLUSION:METH may promote M1 polarization and glycolytic activity in microglia by activating LIPH/LPA/PI3K/AKT signaling, thus promoting the progression of PD.

Deep brain stimulation (DBS) is an established therapy for Parkinson’s disease, yet conventional onsite programming mandates frequent travel to specialized centres, imposing substantial burdens on patients. Here we present a large real-world analysis of remote programming (RP) for DBS in China, drawing on 20,383 patients with Parkinson’s disease and 42,163 RP sessions (2012–2024). RP achieves comparable satisfaction and effectiveness to onsite programming while reducing the healthcare access inequality index by 30%. These access gains translate into disproportionate economic benefits for the most vulnerable groups, with cost savings two to ten times greater among low-income, remote and advanced-disease populations. Integrated clinical–labour–economy modelling projects annual direct economic benefits of ¥1.09 billion from reduced domestic medical tourism and ¥8.15 billion from labour-cost savings, with cumulative benefits of ¥115–270 billion by 2050 (3.9–9.2% of China’s 2024 basic medical insurance fund). These findings suggest that RP could be a clinically equivalent, more equitable and economically advantageous approach for postoperative DBS management worldwide. After more than 10 years of real-world deployment involving 20,383 patients, this analysis reports on the cost-effectiveness of remote programming of deep brain stimulation, outlining the implications for reducing inequalities in healthcare access and projecting scenarios of large-scale implementation in the context of an ageing population.

Reliable blood-based biomarkers for Parkinson’s disease (PD) are needed for minimally invasive diagnosis. We identified a synergistic mRNA biomarker pair, AP3B1 and BMPR2, detectable in blood through an integrative multi-omics workflow. DEGs from a meta-analysis of PD versus healthy controls (HCs) were intersected with DEG-enriched pathway genes and analysed via three-step SMR to identify PD risk candidates, from which machine learning (SVM-RFE and random forest) prioritized AP3B1 and BMPR2. Knockdown of each gene in SH-SY5Y-derived neurons reproduced Parkinsonian phenotypes, with protein docking and co-immunoprecipitation suggesting a direct interaction. An XGBoost model built on PPMI blood RNA-seq (n = 2585) using 25 established PD biomarkers (baseline AUC ~ 0.595) improved to 0.745 with addition of both AP3B1 and BMPR2. qRT-PCR in a cohort of clinical blood samples confirmed their downregulation in PD. These findings support AP3B1 and BMPR2 as a synergistic biomarker pair with speculative biological relevance and possible translational potential.

Glioblastoma (GBM) is a kind of intractable brain tumor. The effect of surgical treatment, radiotherapy and chemotherapy is not ideal. TRF1 is one of the important components of shelterin complex, which plays an important role in human telomere protection. Previous studies have reported that inhibition of TRF1 expression can inhibit the growth and proliferation of GBM without causing serious physiological dysfunction. However, the specific mechanism of inhibition of GBM growth and proliferation caused by decreased TRF1 expression has not been fully elucidated. To further elucidate this mechanism, we knockdown TRF1 by siRNA. We detected the levels of cell senescence, autophagy through biological experiments. It has been found that the knockdown of TRF1 can cause significant increase in the aging, autophagy of GBM. In addition, SIRT-6 is a NAD+- dependent deacetylase. Previous studies have reported that SIRT-6 can maintain the stability of telomere function. Moreover, telomere dysfunction can cause the decrease of SIRT-6 expression. Therefore, we want to study the effect of SIRT-6 expression level on TRF1 knockdown induced aging, autophagy in GBM. The experimental results showed that the knockdown of TRF1 caused the decrease of SIRT-6 expression level, and the increase of SIRT-6 expression level could inhibit the aging, autophagy caused by TRF1 knockdown. This study provides a new direction for the treatment of GBM.

BACKGROUND:Microglial autophagy is closely related to the development of Parkinson's disease (PD). The objective of this research was to investigate the effect of glycyrrhizin (Gly) combined with electroacupuncture (EA) on PD mice and its potential regulation of microglial autophagy. METHODS:A PD mouse model was constructed using the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), followed by the administration of Gly to PD mice and EA. The activation of BV2 cells was triggered by lipopolysaccharide (LPS). Western blotting, immunofluorescence, flow cytometry, Nissl staining, and immunohistochemistry were used to investigate the molecular mechanism that governs how microglial autophagy levels influence PD progression. RESULTS:Elevated levels of HMGB1 were observed in both patients with PD and PD mice. Gly inhibited HMGB1 expression and extracellular secretion by increasing SIRT1 activity and subsequently inhibit BV2 autophagy. EA inhibited the autophagy of microglia in PD mice by inhibiting the activation of TRPV1 and reducing the expression of HMGB1 in vivo. Gly combined with EA downregulated HMGB1 expression, inhibited microglial autophagy and improved the PD process, resulting in better effects than Gly or EA alone. CONCLUSION:Gly combined with EA can reduce the level of autophagy in microglia by downregulating HMGB1, thereby improving the PD process and providing a theoretical basis for the clinical treatment of PD.

BackgroundDeep brain stimulation is a primary surgical treatment for advanced Parkinson’s disease (PD). The globus pallidus interna (GPi) is a key target for this procedure. The posterior subthalamic area (PSA) serves as an effective target for tremor-dominant Parkinson’s disease. However, it is less commonly utilized in conventional DBS surgery compared to the subthalamic nucleus (STN) or the ventral intermediate nucleus (VIM). There is currently no clinical research on the combined DBS surgery targeting both the PSA and the GPi, which is why we have conducted this study.Case reportWe introduced a case of a patient with advanced PD. Due to the patient’s primary manifestations of right-sided tremor and left-sided rigidity, along with significant dyskinesia on the left side, DBS implantation was performed in the left hemisphere targeting the PSA and in the right hemisphere targeting the GPi. The patient’s UPDRS-III score decreased from 73 to 46 postoperatively, showing an improvement of approximately 36.99%, while the H-Y stage improved from stage 4 to 2.5, representing a 37.5% improvement. During the 6-months postoperative follow-up, the patient’s PD symptoms were effectively controlled, with no significant adverse effects.DiscussionWhen advanced PD patients present with asymmetric and variable motor symptoms, combined DBS stimulation targeting both the GPi and the PSA is a viable treatment option.

Parkinson’s disease (PD) is the second most common neurodegenerative disease worldwide and severely affects the physical and mental health of patients. The protein arginine methyltransferase 5 (PRMT5) has been shown to be associated with neuronal degeneration in PD, but its specific mechanism of mediating PD remains unclear. The purpose of this study was to investigate the role of PRMT5 in PD and its potential mechanism. PD models in rats and MN9D cells were induced by 6-hydroxydopamine (6-OHDA). Key genes and proteins were identified through real-time quantitative polymerase chain reaction (RT‒qPCR), Western blotting, and immunofluorescence staining; apoptosis levels were measured using flow cytometry; autophagosome formation was observed via monodansylcadaverine (MDC) staining; and neuronal damage in PD rats was evaluated using hematoxylin‒eosin (H E) and Nissl staining. In this study, we found that PRMT5 levels were elevated in the peripheral blood of PD patients and in 6-OHDA-induced rat brain tissue and MN9D cells and that the expression of PRMT5 was positively correlated with the level of α-Syn. After PRMT5 was knocked down, α-Syn levels in PD rats decreased, neuronal damage was inhibited, and motor disorders improved. In addition, knockdown of PRMT5 promoted 6-OHDA-induced MN9D cell proliferation, inhibited apoptosis, and upregulated autophagy. Mechanistically, PRMT5 inhibits the activation of the Wnt/β-catenin signaling pathway through H3R8me2s modification to stabilize the expression of DKK1, thus inhibiting neuronal autophagy and promoting the development of PD. Our study suggests that PRMT5 may be a potential intervention target for improving PD progression.

Deep brain stimulation (DBS) is a common therapy for managing Parkinson’s disease (PD) in clinical practice. However, a complete understanding of its mode of action is still needed. DBS is believed to work primarily through electrical and neurochemical pathways. Furthermore, DBS has other mechanisms of action. This review explores the fundamental concepts and applications of DBS in treating PD, including its mechanisms, clinical implications, and recent research.

Glioblastoma (GBM) cells have the potential to switch from being “proliferative cells” to peritumoral “invasive cells”. Peritumoral GBM cells have highly invasive properties that allow them to survive surgery, leading to recurrence. The mechanisms underlying the manner in which the tumor microenvironment (TME) regulates the invasiveness of GBM remain unclear. Single-cell RNA sequencing analysis revealed heterogeneity in GBM cells, microglia and macrophages. In this study, the Oncostatin M receptor (OSMR) and leukemia inhibitory factor receptor (LIFR) expression indicated higher invasiveness in core GBM cells. Under environmental stress, the expression of OSMR and LIFR were up-regulated with the effect of hypoxic, acidic, and low-glucose conditions in vitro. Functional experiments revealed that TME stress significantly influences the proliferation, migration and invasion of GBM cells. The differences in core/peripheral TMEs in GBM affected the invasive properties, indicating the significant role of OSMR expression within the TME in tumor progression and postoperative therapy.

The morbidity and mortality associated with vascular cognitive impairment (VCI) generally increase steeply, and health systems will face increasing demand for services. The present study aims to screen key genes to give new insight into the mechanisms and treatment of VCI based on bioinformatic approaches combined with biological experiments in rats. The gene expression data of VCI patients contained in the GSE122063 data set were downloaded from the Gene Expression Omnibus. We performed a weighted gene co-expression network analysis to identify a hub module and 44 hub genes. Two hundred and seventy-seven differentially expressed genes (DEGs) were analyzed using R software by the "limma" package. STRING database was used to construct protein-protein interaction (PPI) network, after which 36 hub genes were identified through Cytoscape. Functional enrichment analysis revealed that these genes from the yellow module and 277 DEGs were mainly associated with these pathways, such as Staphylococcus aureus infection, complement, and coagulation cascades. These biological functions are related to inflammatory cell activation and inflammatory response. The key genes of VCI were the overlapping hub genes from the yellow module and the PPI network. The expressions of hub genes in rats were determined by quantitative reverse transcription-polymerase chain reaction, Western blot, immunohistochemistry, and immunofluorescence. In conclusion, C1QA, C1QB, C1QC, CD163, and FCGR2A were highly expressed in the hippocampus of VCI rats, and they can serve as candidate biomarkers for the diagnosis and prognosis of VCI. Finally, molecular docking results suggested that 5 genes interact with Bisphenol A. These findings open a new avenue to investigate molecular mechanisms for preventing or treating VCI.

Parkinson's disease (PD) is a neurodegenerative disease that mainly manifests as cognitive decline and motor dysfunction, the treatment of which is still a major challenge in the clinical field. Acupuncture therapy has been shown in many studies to enhance the body's own immunity and disease resistance. This study mainly discusses the specific mechanism underlying electroacupuncture intervention in improving PD. Male C57BL/6 mice were intraperitoneally injected with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) to induce a mouse PD model, and the chorea trembling control area of the head of PD mice was treated by electroacupuncture. Western blotting was used to detect the expression of related proteins in mouse pathological samples; TUNEL measured neuronal apoptosis levels; Nissl staining observed neuronal damage; immunofluorescence and immunohistochemistry were used to detect the expression of Iba-1, TH, and α-syn in substantia nigra denser (SN). The expression levels of oxidative stress factors and inflammatory factors were measured by kits. Flow cytometry measured mitochondrial membrane potential and Ca2+ levels. MPTP intraperitoneal injection induced an increase in inflammatory factors in PD mice and promoted the oxidative stress response, and the inflammatory response was alleviated after electroacupuncture treatment. Electroacupuncture intervention effectively alters the decrease in oxidative stress levels and alleviates neuronal damage in PD mice. Electroacupuncture improves mitochondrial dysfunction induced by MPTP in PD mice by activating the SIRT1/AMPK signaling pathway. We also confirmed that knocking down TRPC1 can inhibit the SIRT1/AMPK signaling pathway, weaken the Ca2+ content in mouse neuronal tissue, and promote cell apoptosis. Electroacupuncture improves neuronal damage and alleviates PD in mice through the TRPC1 and SIRT1/AMPK signaling pathways. In addition, electroacupuncture therapy can improve MPTP-induced mitochondrial dysfunction in PD mice and alleviate the PD process.

Background: Parkinson's disease (PD) is a common central neurodegenerative disease in middle-aged and elderly people. The progressive degeneration and death of dopaminergic neurons leads to insufficient dopamine (DA) neurotransmitters. Acupuncture and moxibustion can alleviate the aging of neurons. Therefore, studying the neuroprotective effects of electroacupuncture (EA) in PD mice is particularly important. Methods: Intraperitoneal injection of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP, 20 mg/kg) was used to establish a PD mouse model, and lipopolysaccharide (LPS) was used to induce microglia polarization. Western blotting, terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling (TUNEL), Nissl staining and immunohistochemistry were used to detect neuronal apoptosis and injury, alpha-syn expression and microglial accumulation in PD mice. In addition, the levels of inflammatory factors were determined using enzyme-linked immunosorbent assay (ELISA). Flow cytometry was used to detect the Ca2+ content. The fluorescein isothiocyanate (FITC) labeling method was used to assess glucose uptake. A reagent kit was used to detect glucose and lactate levels. Results: MPTP induced the selective loss of DA neurons in the SN of mice, altered Ca2+ homeostasis, and induced an inflammatory response. In addition, maintaining Ca2+ homeostasis depends on the activity of transient receptor potential channel 1 (TRPC1). EA therapy promotes TRPC1 expression, which has a negative regulatory effect on sodium-glucose cotransporter 1 (SGLT1). Under the action of EA, TRPC1 protein expression increased, Ca2+ concentrations increased, and the effect of SGLT1 was inhibited, thereby facilitating glucose metabolism, blocking the activation of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) pathway, restraining M1 polarization of microglia, and alleviating the PD process. Conclusion: EA promotes TRPC1/Ca2+ pathway activation, inhibits SGLT1-mediated regulation of glucose metabolism and PI3K/AKT pathway activation, inhibits microglial M1 polarization, and alleviates PD.

Background: Parkinson' s disease (PD) is a progressive neurodegenerative disease featured neuropathologically by the loss of dopaminergic neurons of the substantia nigra (SN). Iron overload in the SN is mainly relative to the pathology and pathogenesis of PD. Postmortem samples of PD has indicated the increased levels of brain iron. However, there is no consensus on iron content through iron-sensitive magnetic resonance imaging (MRI) techniques and the alteration of iron and iron related metabolism markers levels in blood and cerebrospinal fluids (CSF) are still unclear based on the current studies. In this study, we performed a meta-analysis to explore the iron concentration and iron metabolism markers levels through iron-sensitive MRI quantification and body fluid.Methods: A comprehensive literature search was performed in PubMed, EMBASE and Cochrane Library databases for relevant published studies that analyzed iron load in the SN of PD patients using quantitative susceptibility mapping (QSM) or susceptibility weighting imaging (SWI), and iron metabolism markers, iron, ferritin, transferrin, total iron-binding capacity(TIBC)in CSF sample or serum/plasma sample (from Jan 2010 to Sep 2022 to filter these inaccurate researches attributed to unadvanced equipment, inaccurate analytical methods). Standardized mean differences (SMD) or mean differences (MD) and 95% confidence intervals (CI) with random or fixed effect model was used to estimate the results. Results: Forty-two articles fulfilled the inclusion criteria including 19 for QSM, 6 for SWI, and 17 for serum/ plasma/CSF sample including 2874 PD patients and 2821 healthy controls (HCs). Our meta-analysis results founded a notable difference for QSM values increase (19.67, 95% CI=18.69-20.64) and for SWI measurements (-1.99, 95% CI= -3.52 to -0.46) in the SN in PD patients. However, the serum/plasma/CSF iron levels and serum/plasma ferritin, transferrin, total iron-binding capacity (TIBC) did not differ significantly between PD patients and HCs.Conclusions: Our meta-analysis showed the consistent increase in the SN in PD patients using QSM and SWI techniques of iron-sensitive MRI measures while no significant differences were observed in other iron metabolism markers levels.

This study aims to elucidate the role of miR-23b-3p in mesenchymal stem cell exosomes in regulating the Wnt signaling pathway to promote autophagy of neurons and alleviate Parkinson's disease (PD) symptoms. We generated rat and cellular PD models with 6-OHDA, treated them with mesenchymal stem cell exosomes rich in miR-23b-3p and determined the expression of α-syn and Wnt/β-catenin pathway and autophagy-related genes. In the plasma of PD patients, the levels of miR-23b-3p and the Wnt/β-catenin pathway-related genes β-catenin and DAT were low, while α-syn expression was high. In the PD cell model, miR-23b-3p was downregulated, the Wnt pathway was inhibited, α-syn was upregulated, neuron autophagy was inhibited, and the revitalization of the Wnt/β-catenin pathway could promote the autophagy of neurons. Coculture of miR-23b-3p-enriched exosomes with MN9D cells confirmed that miR-23b-3p-enriched exosomes could promote autophagy in MN9D cells in a PD cell model. Moreover, animal experiments confirmed the results of the cell experiments. Therefore, miR-23b-3p-enriched mesenchymal stem cell exosomes promote neuronal autophagy by regulating the Wnt signaling pathway, thus alleviating PD progression and providing an important basis for the clinical treatment of PD.

Crizanlizumab is a recent FDA approved humanized IgG2 anti-P-selectin antibody to decrease the frequency of vaso-occlusive crisis VOCs in Sickle cell disease (SCD) patients. Inclacumab is a full human IgG4 monoclonal antibody that selectively targets P-selectin. Anti-cell adhesion effects of Inclacumab were first reported in patients with cardiovascular disease. Two phase 3 clinical trials are evaluating the efficacy of Inclacumab in SCD patients to reduce VOCs

Parkinson's disease (PD) is a neurodegenerative disorder characterized by the gradual death of dopaminergic neurons. Brain-derived neurotrophic factor (BDNF) and its receptors are widely distributed throughout the central nervous system, which can promote the survival and growth of neurons and protect neurons. This study revealed that BDNF promotes STAT3 phosphorylation and regulates autophagy in neurons. The PD mouse model was established by 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Moreover, SH-SY5Y cells were treated with 1-methyl-4-phenyl-pyridinium (MPP+) to establish a PD cell model. The level of BDNF was low in PD model mice and SH-SY5Y cells treated with MPP+. BDNF enhanced the levels of p-TrkB, P-STAT3, PINK1, and DJ-1. BDNF promoted autophagy, inhibited the level of p-α-syn (Ser129) and enhanced cell proliferation. The autophagy inhibitor 3-Methyladenine (3-methyladenine, 3-MA) reversed the protective effects of BDNF on neurons. BiFC assay results showed that there was a direct physical interaction between BDNF and STAT3, and coimmunoprecipitation experiments indicated an interaction between STAT3 and PI3K. The PI3K agonist Recilisib activated the PI3K/AKT/mTOR pathway, promoted autophagy, and alleviated neuronal cell damage. BDNF alleviates PD pathology by promoting STAT3 phosphorylation and regulating neuronal autophagy in SH-SY5Y cells and cultured primary neurons. Finally, BDNF has neuroprotective effects on PD model mice.

Background:Gastric cancer (GC) is an aggressive malignancy with a high mortality rate and poor prognosis. Telomeric repeat-binding factor 2 (TRF2) is a critical telomere protection protein. Emerging evidence indicates that TRF2 may be an essential treatment option for GC; however, the exact mechanism remains largely unknown.Objective:We aimed to explore the role of TRF2 in GC cells. The function and molecular mechanisms of TRF2 in the pathogenesis of GC were mainly discussed in this study.Methods:Relevant data from GEPIA and TCGA databases regarding TRF2 gene expression and its prognostic significance in GC samples were analyzed. Analysis of 53BP1 foci at telomeres by immunofluorescence, metaphase spreads, and telomere-specific FISH analysis was carried out to explore telomere damage and dysfunction after TRF2 depletion. CCK8 cell proliferation, trypan blue staining, and colony formation assay were performed to evaluate cell survival. Apoptosis and cell migration were determined with flow cytometry and scratch-wound healing assay, respectively. qRT-PCR and Western blotting were carried out to analyze the mRNA and protein expression levels after TRF2 depletion on apoptosis, autophagic death, and ferroptosis.Results:By searching with GEPIA and TCGA databases, the results showed that the expression levels of TRF2 were obviously elevated in the samples of GC patients, which was associated with adverse prognosis. Knockdown of TRF2 suppressed the cell growth, proliferation, and migration in GC cells, causing significant telomere dysfunction. Apoptosis, autophagic death, and ferroptosis were also triggered in this process. The pretreatment of chloroquine (autophagy inhibitor) and ferrostatin-1 (ferroptosis inhibitor) improved the survival phenotypes of GC cells.Conclusion:Our data suggest that TRF2 depletion can inhibit cell growth, proliferation, and migration through the combined action of ferroptosis, autophagic death, and apoptosis in GC cells. The results indicate that TRF2 might be used as a potential target to develop therapeutic strategies for treating GC.