Explore the vast range of titles available.

Parkinson's disease (PD) is a neurodegenerative disease characterized by the degeneration of dopaminergic neurons in the substantia nigra (SN); the etiology and pathological mechanism of the disease are still unclear. Recent studies have shown that the activation of a neuroimmune response plays a key role in the development of PD. Alpha-synuclein (α-Syn), the primary pathological marker of PD, can gather in the SN and trigger a neuroinflammatory response by activating microglia which can further activate the dopaminergic neuron’s neuroimmune response mediated by reactive T cells through antigen presentation. It has been shown that adaptive immunity and antigen presentation processes are involved in the process of PD and further research on the neuroimmune response mechanism may open new methods for its prevention and therapy. While current therapeutic regimens are still focused on controlling clinical symptoms, applications such as immunoregulatory strategies can delay the symptoms and the process of neurodegeneration. In this review, we summarized the progression of the neuroimmune response in PD based on recent studies and focused on the use of mesenchymal stem cell (MSC) therapy and challenges as a strategy of disease-modifying therapy with multiple targets.

Lung adenocarcinoma (LUAD) is most common pathological type of lung cancer. LUAD with brain metastases (BMs) usually have poor prognosis. To identify the potential genetic factors associated with BM, a genomic comparison for BM cerebrospinal fluid (CSF) and primary lung tumor samples obtained from 1082 early- and late-stage LUAD patients was performed. We found that single nucleotide variation (SNV) of EGFR was highly enriched in CSF (87% of samples). Compared with the other primary lung tissues, copy number gain of EGFR (27%), CDK4 (11%), PMS2 (11%), MET (10%), IL7R (8%), RICTOR (7%), FLT4 (5%), and FGFR4 (4%), and copy number loss of CDKN2A (28%) and CDKN2B (18%) were remarkably more frequent in CSF samples. CSF had significantly lower tumor mutation burden (TMB) level but more abundant copy number variant. It was also found that the relationships among co-occurrent and mutually exclusive genes were dynamically changing with LUAD development. Additionally, CSF (97% of samples) harbored more abundant targeted drugs related driver and fusion genes. The signature 15 associated with defective DNA mismatch repair (dMMR) was only identified in the CSF group. Cancer associated pathway analysis further revealed that ErbB (95%) and cell cycle (84%) were unique pathways in CSF samples. The tumor evolution analysis showed that CSF carried significantly fewer clusters, but subclonal proportion of EGFR was remarkably increased with tumor progression. Collectively, CSF sequencing showed unique genomic characteristics and the intense copy number instability associated with cell cycle disorder and dMMR might be the crucial genetic factors in BM of LUAD.

Glioma is an extremely aggressive malignant neoplasm of the central nervous system. MicroRNA (miRNA) are known to bind to specific target mRNA to regulate post-transcriptional gene expression and are, therefore, currently regarded as promising biomarkers for glioma diagnosis and prognosis. The aim of the present study was to examine the pathogenesis and potential molecular markers of glioma by comparing the differential expression of miRNA and mRNA between glioma tissue and peritumor brain tissue. We explored the impact of screened core miRNA and mRNA on cell proliferation, invasion, and migration of glioma. An miRNA expression profile dataset (GSE90603) and a transcriptome profile dataset (GSE90598) were downloaded from combined miRNA-mRNA microarray chips in the Gene Expression Omnibus (GEO) database. Overall, 59 differentially expressed miRNAs (DEMs) and 419 differentially expressed genes (DEGs) were identified using the R limma software package. FunRich software was used to predict DEM target genes and miRNA-gene pairs, and Perl software was used to find overlapping genes between DEGs and DEM target genes. There were 129 overlapping genes regulated by nine miRNAs between target genes of the DEMs and DEGs. The Chinese Glioma Genome Atlas(CGGA) was analyzed in order to identify miRNAs with diagnostic and prognostic significance. MiR-139-5p, miR-137, and miR-338-3p were validated to be significantly linked to prognosis in glioma patients. Finally, we validated that miR-139-5p affected glioma malignant biological behavior via targeting gamma-aminobutyric acid A receptor alpha 1(GABRA1) through rescue experiments. Low miR-139-5p expression was correlated with survival probability and World Health Organization (WHO) grade. MiR-139-5p overexpression inhibited cell proliferation, migration, and invasion of glioma in vitro. GABRA1 was identified as a functional downstream target of miR-139-5p. Decreased GABRA1 expression was related to similar biological roles as miR-139-5p overexpression while upregulation of GABRA1 effectively reversed the inhibition effects of miR-139-5p. These results demonstrate a novel axis for miR-139-5p/GABRA1 in glioma progression and provide potential prognostic predictors and therapeutic target for glioma patients.

Rheumatoid arthritis (RA) is a complex and not fully understood autoimmune disease associated with multijoint damage. The main effector cells, the synovial fibroblasts, are apoptosis resistant and hyperplastic which indicate that autophagy level is high in synovial tissue. Real-time PCR, immunocytochemistry, and western blotting were used in this paper to study the autophagy status of the synovial tissues obtained from RA and OA patients at the time of joint replacement surgery. We further evaluated the correlation between autophagy levels with RA activity-associated serum markers with SPSS. The results showed that the expression levels (both in mRNA and in protein level) of autophagy-related proteins (belcin1, Atg5, and LC3) in the synovial tissue of patients with active rheumatoid arthritis (n=20) were significantly higher than those in OA patients (n=16). We further showed that the LC3-II/β-actin relative gray value was strongly correlated with the serum levels of several RA activity-related markers: CRP, ESR, CCP, and RF. Our results indicate that evaluating the autophagy level of synovial biopsies might be a useful way to diagnose RA and to estimate the disease activity. Reducing the expression level of autophagy-related genes might become a new therapeutic target for active rheumatoid arthritis.

Background Cerebral ischemia / reperfusion injury can induce nerve cell apoptosis and ferroptosis and activation of the neuroinflammatory cascade plays a critical role in ischemic stroke progression. Mesenchymal stem cells (MSCs) can aid in repairing nerve injuries and regulating inflammatory responses, but their roles in ischemic stroke are unknown. Methods Here, we investigate the impact of microglial susceptibility to ferroptosis on neuronal apoptosis using an oxygen-glucose deprivation/reperfusion (OGD/R) model. Furthermore, we examined the effects of hypoxia-preconditioned olfactory mucosa mesenchymal stem cells (hOM-MSCs) on attenuating microglial ferroptosis and improving neuroinflammatory response in models of OGD/R and middle cerebral artery occlusion (MCAO). Results Firstly, it has been confirmed that the susceptibility of microglial to ferroptosis significantly amplifies their neuroinflammatory response, thereby accelerating neuronal apoptosis in the OGD/R model. A functional assay identified that the core functional factor, peroxisome proliferator-activated receptor-γ co-activator-1α (PGC-1α), secreted from hOM-MSCs has a critical role in the hOM-MSC-modulated recovery of cellular activity in neurons. This discovery was accomplished through inhibiting microglia ferroptosis and the enhancement of immune regulation in the area affected by an infarct, all of which are closely linked to neuroinflammatory reactions. Mechanistically, exposure to hOM-MSCs partially mediates the amelioration of neuroinflammatory response and restoration of neural function in ischemic stroke by means of PGC-1α activation within the infarct region, via initiation of the PPARα-GPX4/ACSL4-NFκB signaling cascades in microglia. Conclusions These findings provide convincing proof that PGC-1α plays a crucial role in facilitating the advantageous impacts of hOM-MSCs on the enhancement of neural functionality following an ischemic stroke. The treatment of hOM-MSC could be a promising and effective neuroprotective candidate to ischemic stroke, and PGC-1α may be used in isolation or in combination with hOM-MSCs for ischemic stroke treatment. Highlights The susceptibility of microglial to ferroptosis significantly amplifies their neuroinflammatory response, thereby accelerating neuronal apoptosis in the OGD/R model. The hOM-MSC enhances neural functionality following an ischemic stroke through attenuating microglial ferroptosis and improving neuroinflammatory response. The hOM-MSCs are partially mediated by PGC-1α through initiation of the PPARα-GPX4/ACSL4-NFκB signaling cascades in microglia. The treatment of hOM-MSC could be a promising and effective neuroprotective candidate to ischemic stroke, and PGC-1α may be used in isolation or in combination with hOM-MSCs for ischemic stroke treatment.

Spinal cord injury (SCI) is a devastating incident that induces neuronal loss and dysfunction. Notoginsenoside R1 (NGR1) has been reported to exhibit a neuroprotective role after SCI. In this study, the effect and molecular mechanisms of NGR1 in models of SCI were further investigated. Rat adrenal pheochromocytoma cell line (PC-12) were stimulated with lipopolysaccharide (LPS) to establish a cell model of SCI-like condition. The changes of proinflammatory cytokines and associated proteins were analyzed using enzyme linked immunosorbent assay (ELISA) and western blotting. A rat model of SCI was established. Nissl staining were used to observe the morphological characteristics of spinal cord tissues. reverse transcription-quantitative PCR (RT-qPCR) was used to measure the expression of miR-301a andKrüppel-like factor 7 (KLF7). Our results showed that NGR1 alleviated LPS-triggered apoptosis and inflammation in PC-12 cells. MiR-301a was upregulated in LPS-stimulated PC-12 cells and was downregulated by NGR1 treatment. MiR-301a overexpression reversed the effect of NGR1 in LPS-treated PC-12 cells. KLF7 was verified to be targeted by miR-301a. NGR1 activated Wnt/β-catenin signaling in LPS-treated PC-12 cells by inhibiting miR-301a and upregulating KLF7. Moreover, blocking wingless/integrated (Wnt)/β-catenin signaling eliminated the protective effect of NGR1 against SCI and . Overall, NGR1 could reduce inflammation and apoptosis and promote functional recovery of SCI rats by activating Wnt/β-catenin pathway.

We study a new problem of location-inventory-routing in forward and reverse logistic (LIRP-FRL) network design, which simultaneously integrates the location decisions of distribution centers (DCs), the inventory policies of opened DCs, and the vehicle routing decision in serving customers, in which new goods are produced and damaged goods are repaired by a manufacturer and then returned to the market to satisfy customers’ demands as new ones. Our objective is to minimize the total costs of manufacturing and remanufacturing goods, building DCs, shipping goods (new or recovered) between the manufacturer and opened DCs, and distributing new or recovered goods to customers and ordering and storage costs of goods. A nonlinear integer programming model is proposed to formulate the LIRP-FRL. A new tabu search (NTS) algorithm is developed to achieve near optimal solution of the problem. Numerical experiments on the benchmark instances of a simplified version of the LIRP-FRL, the capacitated location routing problem, and the randomly generated LIRP-FRL instances demonstrate the effectiveness and efficiency of the proposed NTS algorithm in problem resolution.

Objective Recurrent high‐grade gliomas have a poor prognosis and limited therapeutic options. This study aimed to evaluate the safety and efficacy of SYHA1813, a dual inhibitor of VEGFR and CSF1R, in patients with recurrent high‐grade gliomas. Methods Eligible patients (aged ≥ 18) with histologically or cytologically confirmed recurrent high‐grade gliomas were included. Patients were administered different doses of SYHA1813 daily to assess its safety and initial efficacy. Results Sixty‐four individuals with high‐grade gliomas were enrolled. Treatment‐related adverse events (TRAEs) were reported in 92.2% of the patients, with 40.6% experiencing grade 3 or higher TRAEs. No grade 5 TRAE was reported. The overall objective response rate (ORR) and disease control rate (DCR) were 18.8% (95% confidence interval [CI], 10.1–30.5) and 51.6% (95% CI, 38.7–64.3), respectively. With a median follow‐up duration of 9.5 months, the median progression‐free survival (PFS) was 2.8 months (95% CI, 2.3–4.2) with PFS‐6 of 22.5% (95% CI, 11.8–35.4) and the median OS was 15.1 months (95% CI, 10.2–NE) with OS‐12 of 63.3% (95% CI, 49.3–74.4). Among the 38 patients with glioblastoma, the ORR was 18.4% (95% CI, 7.7–34.3), with a DCR of 52.6% (95% CI, 35.8–69.0). The median PFS and OS were 4.1 months (95% CI, 2.3–5.3) and 13.0 months (95% CI, 9.1–NE), respectively. SYHA1813 was detected in cerebrospinal fluid samples and the drug concentration to plasma free drug concentration ratio was 0.30–1.27. Interpretation SYHA1813 exhibits encouraging anti‐tumor activity with a manageable safety profile for the treatment of recurrent high‐grade gliomas, especially glioblastoma. Trial Registration chictr.org.cn (ChiCTR2100045380)

Glioblastoma has a poor prognosis and is one of the most lethal types of cancer in the world. TP53 induced glycolysis regulatory phosphatase (TIGAR) is upregulated in various types of cancer. Therefore, the present study investigated the role of TIGAR in glioblastoma. TIGAR expression was measured in glioma samples and cell lines using immunohistochemistry and western blotting. Reduced nicotinamide adenine dinucleotide phosphate (NADPH), glutathione, malondialdehyde and intracellular reactive oxygen species levels were detected to measure oxidative stress in U-87MG cells following short hairpin RNA (shRNA)-mediated knockdown of TIGAR. Cell viability was determined using an MTT assay for TIGAR-overexpression vector- and TIGAR-shRNA-transfected U-87MG cells. Apoptosis was assessed to evaluate whether TIGAR knockdown sensitized cells to the antitumor effects of temozolomide (TMZ). Migration, invasion and epithelial-mesenchymal transition (EMT) were further assessed using Transwell and western blotting assays. A co-immunoprecipitation assay was used to detect the interaction between TIGAR and protein kinase B (AKT). The results of the present study revealed that TIGAR was positively associated with poor survival and was upregulated in glioblastoma. TIGAR knockdown significantly increased oxidative stress, decreased cell proliferation and exacerbated TMZ-induced apoptosis in U-87MG cells. Additionally, TIGAR knockdown decreased migration, invasion and EMT, and treatment of TIGAR-shRNA-transfected cells with NADPH had no effect on metastasis. In addition, TIGAR promoted AKT activation and bound to AKT. In conclusion, the present study demonstrated that TIGAR may promote glioblastoma growth and progression through oxidation resistance and AKT activation.

Environmental regulations have led to firms considering offshoring their production to avoid compliance costs. However, overseas production comes with yield uncertainty. This study examines optimal environmental regulations and firms’ responses under three production scenarios. The government’s objective is to maximize social welfare by selecting the type and intensity of regulatory instruments, while firms seek to optimize profits by adjusting their optimal production quantities. Our analysis finds that price and quantity regulation instruments have similar impacts on social welfare, but firms prefer quantity instruments despite price instruments being more beneficial for consumers. Furthermore, both pollution damage coefficient and yield uncertainty are important factors affecting social welfare and firms’ location choice and there exist win–win situations that benefit the government, firms, and consumers. Additionally, offshoring tends to be more environmentally friendly to the local environment. To further validate the main model, we examine various extensions. Results show that the hybrid instrument does not significantly enhance social welfare, but it does offer flexibility in adjusting firms’ production transfer motivations. Additionally, factors such as positive production and fixed costs, as well as multi-market issues, do not alter the government’s preference for regulatory instruments.