LncRNA CEBPA-AS1 alleviates cerebral ischemia-reperfusion injury by sponging miR-340-5p regulating APPL1/LKB1/AMPK pathway.

Long non-coding RNAs (lncRNAs) regulate neurological damage in cerebral ischemia-reperfusion injury (CIRI). This study aimed to investigate the biological roles of lncRNA CEBPA-AS1 in CIRI. Middle cerebral artery occlusion and ischemia-reperfusion injury (MCAO/IR) rat model and oxygen-glucose deprivation and reoxygenation (OGD/R) cell lines were generated; the expression of CEBPA-AS1 was evaluated by qRT-PCR. The effects of CEBPA-AS1 on cell apoptosis and nerve damage were examined. The downstream microRNA (miRNA) and mRNA of CEBPA-AS1 were predicted and verified. We found that overexpression of CEBPA-AS1 could attenuate MCAO/IR-induced nerve damage and neuronal apoptosis in the rat model. Knockdown of CEBPA-AS1 aggravated cell apoptosis and enhanced the production of LDH and MDA in the OGD/R cells. Upon examining the molecular mechanisms, we found that CEBPA-AS1 stimulated APPL1 expression by combining with miR-340-5p, thereby regulating the APPL1/LKB1/AMPK pathway. In the rescue experiments, CEBPA-AS1 overexpression was found to attenuate OGD/R-induced cell apoptosis and MCAO/IR induced nerve damage, while miR-340-5p reversed these effects of CEBPA-AS1. In conclusion, CEBPA-AS1 could decrease CIRI by sponging miR-340-5, regulating the APPL1/LKB1/AMPK pathway.

Renal Clearable Ultrasmall Single-Crystal Fe Nanoparticles for Highly Selective and Effective Ferroptosis Therapy and Immunotherapy.

Iron-based nanoparticles have attracted much attention because of their ability to induce ferroptosis via a catalyzing Fenton reaction and to further potentiate immunotherapy. However, current iron-based nanoparticles need to be used in cooperation with other treatments or be applied in a high dose for effective therapy because of their low reactive oxygen species production efficacy. Here, we synthesized ultrasmall single-crystal Fe nanoparticles (bcc-USINPs) that stayed stable in a normal physiological environment but were highly active in a tumor microenvironment because of the selective acidic etching of an Fe3O4 shell and the exposure of the Fe(0) core. The bcc-USINPs could efficiently induce tumor cell ferroptosis and immunogenetic cell death at a very low concentration. Intravenous injection of iRGD-bcc-USINPs at three doses of 1 mg/kg could effectively suppress the tumor growth, promote the maturation of dendritic cells, and trigger the adaptive T cell response. Combined with programmed death-ligand 1 (PD-L1) immune checkpoint blockade immunotherapy, the iRGD-bcc-USINP-mediated ferroptosis therapy greatly potentiated the immune response and developed strong immune memory. In addition, these USINPs were quickly renal excreted with no side effects in normal tissues. These iRGD-bcc-USINPs provide a simple, safe, effective, and selectively tumor-responsive Fe(0) delivery system for ferroptosis-based immunotherapy.

Association of Polymorphisms of Mismatch Repair Genes hMLHI and hMSH2 with Breast Cancer Susceptibility: A Meta-Analysis.

This article serves to evaluate the association of polymorphisms of mismatch repair genes (hMLH1 and hMSH2) with breast cancer (BC) susceptibility through a meta-analysis. Our methods involved extensive research in Chinese and English databases that examined the association of hMLH1 and hMSH2 polymorphisms with susceptibility to BC, strictly abiding by established inclusion and exclusion criteria. Software Stata 12.0 was used for statistical data analysis. A total of 12 studies were available for meta-analysis, published between 2014 and 2017, of which respectively 9 studies explored the association of hMLH1 (rs1799977 A > G and rs63750447 T > A) and 3 studies explored the association of hMSH2 (rs4987188 [Gly322Asp] and rs17217772 [Asn127Ser]) with patients' susceptibility to BC. The results showed that both the rs1799977 A > G polymorphism GA + GG genotype (especially in the Caucasian population) and the rs63750447 T > A polymorphism TA + AA genotype in the hMLH1 gene increased patients' susceptibility to BC. The genotype detection method was selected as a target for subgroup analysis. According to studies where MassARRAY assay was conducted, the rs1799977 A > G polymorphism was correlated with BC susceptibility in the dominant model, while rs4987188 (Gly322Asp) and rs17217772 (Asn127Ser) of the hMSH2 gene presented no observable correlation with the risk for BC. Both the rs1799977 A > G and rs63750447 T > A polymorphisms in the hMLH1 gene showed a significant association with a markedly increased risk for BC, while rs4987188 (Gly322Asp) and rs17217772 (Asn127Ser) of the hMSH2 gene were not clearly correlated with BC susceptibility.

Plasma miR-513a-5p as a Potential Biomarker for Diagnosis of Nonalcoholic Fatty Liver Disease in Type 2 Diabetes Mellitus Patients.

BACKGROUND: The current study aims to investigate the relationship between plasma levels of miR-513a-5p and lipid metabolism and insulin resistance in patients with type 2 diabetes mellitus (T2DM) and nonalcoholic fatty liver disease (NAFLD). METHODS: Two hundred patients with T2DM were selected, including 104 patients with NAFLD diagnosed by ultrasound and 96 patients without NAFLD. They were divided into combined group (T2DM/NAFLD) and control group (T2DM). Height, weight, blood lipid, and blood sugar were measured. Additionally, body mass index (BMI) and homeostasis model assessment of insulin resistance (HOMA-IR) index were calculated. RT-PCR was carried out to analyze the level of plasma miR-513a-5p. The correlation between plasma miR-513a-5p level and clinical indicators was analyzed by Pearson's correlation assay. RESULTS: Compared with the T2DM group, BMI, AST, ALT, TG, GGT, LDL-C, 2hPBG, Fins, 2hIns, HbAIc (%), and HOMA-IR were significantly increased in the T2DM/NAFLD group, and plasma miR-513a-5p levels were significantly decreased. Pearson's correlation analysis showed that miR-513a-5p was negatively correlated with ALT, LDL-C, 2h Ins, and HomA-IR. Receiver operating characteristic (ROC) analysis showed plasma miR-513a-5p could differentiate T2DM/NAFLD patients from NAFLD patients. CONCLUSIONS: Decreased plasma miR-513a-5p level may act as a potential biomarker for diagnosis of NAFLD in T2DM patients.

Nrdp1-mediated Macrophage Phenotypic Regulation Promotes Functional Recovery in Mice with Mild Neurological Impairment after Intracerebral Hemorrhage.

Neuregulin receptor degradation protein 1 (Nrdp1) is a ring finger E3 ubiquitin ligase involved in some inflammation through ubiquitination, including macrophage polarization following cerebral hemorrhage. However, there is limited understanding regarding the mechanisms through which Nrdp1 modulates macrophage polarization and the potential impact of this modulation on neurological function. Using stereotactic injection and adenoviral transfection techniques, the corresponding animal models were constructed through injecting adenovirus, saline, or blood into the mouse striatum at different periods of time in this research. The alteration in the ratio of various M1/M2 phenotype-associated markers (e.g., CD86, CD206, IL-6, IL-10, etc.) was evaluated through immunohistochemistry, immunofluorescence, western blotting, and elisa assays. Additionally, neurological function scores and behavioral tests were utilized to evaluate changes in neurological function in mice after cerebral hemorrhage. Our results show that overexpression of Nrdp1 promotes the expression of a variety of M2 macrophage-associated markers and enhance transcriptional activity of arginase-1 (Arg1) protein through ubiquitination for early regulation M2 macrophage polarization. Additionally, Nrdp1 promotes hematoma absorption, increases IL-10 expression, inhibits inducible nitric oxide synthase (iNOS), IL-6, and TNF-α production, alleviates neurological impairment and brain edema, and accelerates functional recovery. These findings suggest that modulating macrophage polarization through Nrdp1 could be a therapeutic strategy for neurofunctional impairment in cerebral hemorrhage.

Renal-clearable porous hollow copper iron oxide nanoparticles for trimodal chemodynamic-photothermal-chemo anti-tumor therapy.

Multifunctional nanoplatforms with the synergistic effects of multiple therapeutic modalities have become a research focus due to their superior anti-tumor properties over single therapeutic modalities. Herein, we developed around 14 nm porous hollow copper iron oxide nanoparticles (PHCuFeNPs) with pore sizes of around 2-3 nm as a cisplatin carrier and photothermal therapeutic agent. The PHCuFeNPs were synthesized via a galvanic reaction between Cu2S nanoparticles and iron pentacarbonyl (Fe(CO)5) followed by etching in the organic phase to make the pores. They were stable under normal physiological conditions, but the pores were etched in a weak acidic tumor microenvironment, resulting in the controlled release of Cu and Fe ions for enhanced chemodynamic therapy and accelerated cisplatin release for chemotherapy. Under 980 nm laser irradiation, the PHCuFeNPs could effectively heat up to further promote the release process for synergistic therapy. Besides, they were proved to mediate immunogenic cell death to activate the immune system for potential immunotherapy. Together with their ability to degrade into fragments for fast renal metabolism, we believe that these PHCuFeNPs could provide a biocompatible and efficient multi-antitumor therapeutic approach.

The Impact of Volume Factor on the Long-Term Outcome of Gamma Knife Radiosurgery for Sporadic Cerebral Cavernous Malformations.

OBJECTIVE: We aimed to evaluate the long-term outcome of gamma knife radiosurgery (GKRS) for the treatment of sporadic cerebral cavernous malformation (CCM), especially the influence of lesion volume on annual hemorrhage rate (AHR) of patients with CCM after GKRS. METHODS: Fifty-one single-lesion patients with a history of hemorrhage who underwent radiosurgery at our institution were included and divided into 2 groups (A and B), based on their lesion volume. Group A included 25 patients with lesion volumes >1 cm3, whereas group B included 26 patients with lesion volumes ≤1 cm3. The clinical data of the patients were retrospectively analyzed. RESULTS: All patients were followed up for more than 4 years after GKRS. The calculated AHR before GKRS was 18.49% in group A and 10.16% in group B. The calculated AHR after GKRS was 5.43% and 0.99% for groups A and B, respectively. Significant differences in AHR after GKRS were identified between group A and group B (P = 0.011). Thirty-seven patients with sporadic CCM (14 in group A, 23 in group B) experienced symptom improvement, and significant differences in symptom improvement were observed between group A and group B (P = 0.009). CONCLUSIONS: GKRS decreased the risk of hemorrhage and was beneficial for symptomatic improvement in patients with sporadic CCM with a history of hemorrhage. The long-term clinical outcomes for patients with sporadic CCM with small lesion volumes (≤1 cm3) were better than those of patients with sporadic CCM with large lesion volumes (>1 cm3).

LncRNA TUG1 inhibits neuronal apoptosis in status epilepticus rats via targeting the miR-421/mTOR axis.

Status epilepticus (SE) induces apoptosis of hippocampal neurons. However, the underlying mechanism in SE is not fully understood. Recently, lncRNA TUG1 is reported as a significant mediator in neuronal development. In present study, we aimed to investigate whether lncRNA TUG1 induces apoptosis of hippocampal neurons in SE rat models. TUG1 expression in serum of normal volunteers and SE patients, SE rats and neurons with epileptiform discharge was detected. SE rat model was established and intervened with TUG1 to evaluate hippocampal neuronal apoptosis. The experiments in vitro were further performed in neurons with epileptiform discharge to verify the effects of TUG1 on neuronal apoptosis of SE rats. The downstream mechanism of TUG1 was predicted and verified. miR-421 was intervened to perform the rescue experiments. Levels of oxidative stress and inflammation-related factors and mTOR pathway-related proteins in SE rats and hippocampal neurons were detected. TUG1 was highly expressed in serum of SE patients, SE rats and neurons with epileptiform discharge. Inhibition of TUG1 relieved pathological injury, oxidative stress and inflammation and reduced neuronal apoptosis in SE rats, which were further verified in hippocampal neurons. TUG1 upregulated TIMP2 expression by targeting miR-421. Overexpressed miR-421 inhibited hippocampal neuronal apoptosis. TUG1 knockout inactivated the mTOR pathway via the miR-421/TIMP2 axis to relieve neuronal apoptosis, oxidative stress and inflammation in SE rats and hippocampal neurons. Taken together, these findings showed that downregulation of lncRNA TUG1 inhibited apoptosis of hippocampal neurons in SE rats, and attenuated oxidative stress and inflammation damage through regulating the miR-421/mTOR axis.