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Background: Lipid droplets (LD), lipid-storing organelles containing neutral lipids like glycerolipids and cholesterol, are increasingly accepted as hallmarks of inflammation. The nuclear paraspeckle assembly transcript 1 (NEAT1), a long non-coding RNA with over 200 nucleotides, exerts an indispensable impact on regulating both LD agglomeration and autophagy in multiple neurological disorders. However, knowledge as to how NEAT1 modulates the formation of LD and associated signaling pathways is limited. Methods: In this study, primary microglia were isolated from newborn mice and exposed to oxygen-glucose-deprivation/reoxygenation (OGD/R). To further explore NEAT1-dependent mechanisms, an antisense oligonucleotide (ASO) was adopted to silence NEAT1 under in vitro conditions. Studying NEAT1-dependent interactions with regard to autophagy and LD agglomeration under hypoxic conditions, the inhibitor and activator of autophagy 3-methyladenine (3-MA) and rapamycin (RAPA) were used, respectively. In a preclinical stroke model, mice received intraventricular injections of ASO NEAT1 or control vectors in order to yield NEAT1 knockdown. Analysis of readout parameters included qRT-PCR, immunofluorescence, western blot assays, and behavioral tests. Results: Microglia exposed to OGD/R displayed a temporal pattern of NEAT1 expression, peaking at four hours of hypoxia followed by six hours of reoxygenation. After effectively silencing NEAT1, LD formation and autophagy-related proteins were significantly repressed in hypoxic microglia. Stimulating autophagy in ASO NEAT1 microglia under OGD/R conditions by means of RAPA reversed the downregulation of LD agglomeration and perilipin 2 (PLIN2) expression. On the contrary, application of 3-MA promoted repression of both LD agglomeration and expression of the LD-associated protein PLIN2. Under in vivo conditions, NEAT1 was significantly increased in mice at 24 h post-stroke. Knockdown of NEAT1 significantly alleviated LD agglomeration and inhibited autophagy, resulting in improved cerebral perfusion, reduced brain injury and increased neurological recovery. Conclusion: NEAT1 is a key player of LD agglomeration and autophagy stimulation, and NEAT1 knockdown provides a promising therapeutic value against stroke. [ABSTRACT FROM AUTHOR]

Hypoxia triggers reactive microglial inflammation and lipid droplet (LD) accumulation under stroke conditions, although the mutual interactions between these two processes are insufficiently understood. Hence, the involvement of transforming growth factor (TGF)-β1 in inflammation and LD accumulation in cultured microglia exposed to hypoxia were analyzed herein. Primary microglia were exposed to oxygen-glucose deprivation (OGD) injury and lipopolysaccharide (LPS) stimulation. For analyzing the role of TGF-β1 patterns under such conditions, a TGF-β1 siRNA and an exogenous recombinant TGF-β1 protein were employed. Further studies applied Triacsin C, an inhibitor of LD formation, in order to directly assess the impact of LD formation on the modulation of inflammation. To assess mutual microglia-to-neuron interactions, a co-culture model of these cells was established. Upon OGD exposure, microglial TGF-β1 levels were significantly increased, whereas LPS stimulation yielded decreased levels. Elevating TGF-β1 expression proved highly effective in suppressing inflammation and reducing LD accumulation in microglia exposed to LPS. Conversely, inhibition of TGF-β1 led to the promotion of microglial cell inflammation and an increase in LD accumulation in microglia exposed to OGD. Employing the LD formation inhibitor Triacsin C, in turn, polarized microglia towards an anti-inflammatory phenotype. Such modulation of both microglial TGF-β1 and LD levels significantly affected the resistance of co-cultured neurons. This study provides novel insights by demonstrating that TGF-β1 plays a protective role against microglia-mediated neuroinflammation through the suppression of LD accumulation. These findings offer a fresh perspective on stroke treatment, suggesting the potential of targeting this pathway for therapeutic interventions. [ABSTRACT FROM AUTHOR]

Stroke is an acute cerebrovascular disease, including ischemic and hemorrhagic stroke. Stroke is the second leading cause of death after ischemic heart disease, which accounts for 9% of the global death toll. To explore the molecular mechanisms of the effects of the dysregulated factors, in the GEO database, we obtained transcriptome data from 24 h/72 h of mice with ischemic stroke and 24 h/72 h of normal mice. We then performed differential gene analysis, coexpression analysis, enrichment analysis, and regulator prediction bioinformatics analysis to identify the potential genes. We made a comparison between the ischemic stroke 72 h and the ischemic stroke for 24 h, and 5103 differential genes were obtained (p < 0.05). Four functional barrier modules were obtained by weighted gene coexpression network analysis. The critical genes of each module were ASTL, Zfp472, Fmr1 gene, and Nap1l1. The results of the enrichment analysis showed ncRNA metabolism, microRNAs in cancer, and biosynthesis of amino acids. These three functions and pathways have the most considerable count value. The regulators of the regulatory dysfunction module were predicted by pivotal analysis of TF and noncoding RNA, and critical regulators including NFKB1 (NF-κB1), NFKBIA, CTNNB1, and SP1 were obtained. Finally, the pivotal target gene found that CTNNB1, NFKB1, NFKBia, and Sp1 are involved in 18, 32, 2, and 60 target genes, respectively. Therefore, we believe that NFKB1 and Sp1 have a potential role in the progression of ischemic stroke. The NFKB signaling pathway promotes inflammatory cytokines and regulates the progression of ischemic stroke. [ABSTRACT FROM AUTHOR]

The efficacy and safety of traditional Chinese medicine (TCM) paired with western medicine in the treatment of patients with COVID-19 remains controversial. This meta-analysis was performed to identify the effects of TCM. Seven electronic databases were reviewed from the inception of these databases to 30 June 2022. A quality assessment of the included studies was performed with the Cochrane Collaboration's tool to provide a score of high, unclear, or low risk of bias. The standard software program (Stata, version 12.0, statistical software) was used for endpoint analyses. A total of 13 RCTs involving 1398 patients conducted in China were included. The cross-sectional data from various studies were plotted, and the results illustrated that the statistically higher rates of total effectiveness (RR, 1.357; 95% CI, 1.259 to 1.464; P < 0.001), improvement of chest CT (RR, 1.249; 95% CI, 1.143 to 1.356; P < 0.001), and cough improvement (RR, 1.228; 95% CI, 1.057 to 1.570; P = 0.012) and a lower incidence of conversion to severe cases (RR, 0.408; 95% CI, 0.275 to 0.605; P < 0.001) were demonstrated in the TCM group than that of the control group. Of note, the subgroup on specific TCM of Lianhua Qingwen (LQ) revealed that the experiment group was associated with a higher rate of total effectiveness (RR, 1.248; 95% CI, 1.136 to 1.371; P < 0.001) and improvement of chest CT (RR, 1.226; 95% CI, 1.110 to 1.356; P < 0.001) and a lower rate of conversion to severe cases (RR, 0.469; 95% CI, 0.311 to 0.707; P < 0.001). However, there was no significant difference in fever improvement (RD, 0.110; 95% CI, -0.063 to 0.283; P = 0.213). The findings of this meta-analysis suggest that TCM combined with western medicine is more effective in treating COVID-19 via relieving symptoms, promoting patients' recovery, and cutting the rate of patients developing into severe conditions. However, given the relevant possible biases in our study, adequately powered and better-designed studies with long-term follow-up are required to reach a firmer conclusion. [ABSTRACT FROM AUTHOR]

Triggering receptor expressed on myeloid cells 2 (TREM2) is a transmembrane receptor protein predominantly expressed in microglia within the central nervous system (CNS). TREM2 regulates multiple microglial functions, including lipid metabolism, immune reaction, inflammation, and microglial phagocytosis. Recent studies have found that TREM2 is highly expressed in activated microglia after ischemic stroke. However, the role of TREM2 in the pathologic response after stroke remains unclear. Herein, TREM2-deficient microglia exhibit an impaired phagocytosis rate and cholesteryl ester (CE) accumulation, leading to lipid droplet formation and upregulation of Perilipin-2 (PLIN2) expression after hypoxia. Knockdown of TREM2 results in increased lipid synthesis (PLIN2, SOAT1) and decreased cholesterol clearance and lipid hydrolysis (LIPA, ApoE, ABCA1, NECH1, and NPC2), further impacting microglial phenotypes. In these lipid droplet-rich microglia, the TGF-β1/Smad2/3 signaling pathway is downregulated, driving microglia towards a pro-inflammatory phenotype. Meanwhile, in a neuron-microglia co-culture system under hypoxic conditions, we found that microglia lost their protective effect against neuronal injury and apoptosis when TREM2 was knocked down. Under in vivo conditions, TREM2 knockdown mice express lower TGF-β1 expression levels and a lower number of anti-inflammatory M2 phenotype microglia, resulting in increased cerebral infarct size, exacerbated neuronal apoptosis, and aggravated neuronal impairment. Our work suggests that TREM2 attenuates stroke-induced neuroinflammation by modulating the TGF-β1/Smad2/3 signaling pathway. TREM2 may play a direct role in the regulation of inflammation and also exert an influence on the post-ischemic inflammation and the stroke pathology progression via regulation of lipid metabolism processes. Thus, underscoring the therapeutic potential of TREM2 agonists in ischemic stroke and making TREM2 an attractive new clinical target for the treatment of ischemic stroke and other inflammation-related diseases. [Display omitted] • TREM2 regulates multiple microglial functions including lipid metabolism, inflammation, and microglial phagocytosis. • TREM2-deficient microglia exhibit an impaired phagocytosis rate and lipid droplet accumulation. • TREM2 knockdown leads lower TGF-β1 levels and less anti-inflammatory M2 phenotype microglia. • TREM2-deficient microglia display a lower neuroprotective potential. • TREM2 regulates post-ischemic inflammation in both a direct and an indirect way by modulating lipid metabolism. [ABSTRACT FROM AUTHOR]

The purpose of this study was to evaluate the efficacy of surgical revascularization versus conservative treatment and different surgical modalities, in order to provide evidence for the patient with moyamoya disease (MMD) to choose the appropriate treatment. We comprehensively searched PubMed, Embase, Web of Science, and the Cochrane Library for articles published regarding MMD treatment. If the I 2 value, which evaluated the heterogeneity, was <50%, a fixed-effect model was used; if not, a random effect model was applied. Twenty-seven articles were included in the meta-analysis. The surgery group is more advantageous in reducing the risk of future stroke events than conservative treatment in MMD patients (odds ratio [OR] 0.26, 95% confidence interval [CI] 0.20–0.33, P < 0.001). In addition, the surgical group also had an advantage in terms of increased cerebral perfusion (OR 7.16, 95% CI 3.28–15.64, P < 0.001) and death due to rebleeding (OR 0.27, 95% CI 0.10–0.72, P < 0.01). Direct surgery showed a significant efficacy over indirect surgery (OR 2.03, 95% CI 1.32–3.13, P < 0.01). No obvious difference was found between the direct and indirect bypass subset (OR 0.76, 95% CI 0.51–1.14, P = 0.185). Angiographic results in patients undergoing direct bypass surgery are more pronounced (OR 0.20, 95% CI 0.06–0.67, P < 0.01). In patients with symptomatic moyamoya disease, bypass surgery is more effective than conservative treatment to prevent future strokes. In surgical patients, direct bypass seems to reduce the risk of stroke more than an indirect bypass. [ABSTRACT FROM AUTHOR]

This review summarizes the implications of the primary tumor suppressor protein phosphatase and tensin homolog (PTEN) in aggressive cancer development. PTEN interacts with other cellular proteins or factors suggesting the existence of an intricate molecular network that regulates their oncogenic function. Accumulating evidence has shown that PTEN exists and plays a role in the cytoplasmic organelles and in the nucleus. PTEN blocks phosphoinositide 3‐kinases (PI3K)–protein kinase B–mammalian target of rapamycin signaling pathway by dephosphorylating phosphatidylinositol (PI)‐3,4,5‐triphosphate to PI‐4,5‐bisphosphate thus counteracting PI3K function. Studies have shown that PTEN expression is tightly regulated at transcriptional, posttranscriptional, and posttranslational levels (including protein–protein interactions and posttranslational modifications). Despite recent advances in PTEN research, the regulation and function of the PTEN gene remain largely unknown. How mutation or loss of specific exons in the PTEN gene occurs and involves in cancer development is not clear. This review illustrates the regulatory mechanisms of PTEN expression and discusses how PTEN participates in tumor development and/or suppression. Future prospects for the clinical applications are also highlighted. [ABSTRACT FROM AUTHOR]

Background: The safety and the benefits of reducing the risk of bleeding complications via protamine administration during the percutaneous coronary intervention (PCI) remains unclear. This study aimed to systematically assessed the efficacy and safety of using protamine in PCI. Method: Potential academic studies were identified from PubMed, Cochrane Library, EMBASE, and Web of Science. The time range we retrieved from was that from the inception of electronic databases to March 31, 2022. Gray studies were identified from the references of included literature reports. Stata version 12.0 statistical software (StataCorp LP) was used to analyze the pooled data. Results: A total of seven studies were involved in our study. The overall participants of the protamine group were 4983, whereas it was 1953 in the nonprotamine group. This meta‐analysis indicated that protamine was preferable for PCI as its lower value of major bleeding (odds ratio [OR] = 0.489, 95% confidence interval [CI]: 0.362–0.661, p <.001) and minor bleeding (OR = 0.281, 95% CI: 0.123–0.643, p =.003). Additionally, the protamine did not tend to be related a higher incidence of mortality (p =.143), myocardial infarction (p =.990), and stent thrombosis (p =.698). Conclusions: Based on available evidence, use of protamine may reduce the risk of bleeding complications without increasing the risk of mortality, myocardial infarction, and stent thrombosis. Given the relevant possible biases in our study, adequately powered and better‐designed studies with long‐term follow‐up are required to reach a firmer conclusion. [ABSTRACT FROM AUTHOR]

Pulmonary fibrosis is a type of chronic, progressive, fibrotic lung disease of unclear cause with few treatment options. Cell therapy is emerging as a promising novel modality for facilitating lung repair. Mesenchymal stem cell (MSC)-based and macrophage-based cell therapies are regarded as promising strategies to promote lung repair, due to incredible regenerative potential and typical immunomodulatory function, respectively. Extracellular vesicles (EVs), including exosomes and microvesicles, are cell-derived lipid-bilayer membrane vesicles that are secreted from virtually every cell and are involved in intercellular communication by delivering expansive biological cargos to recipients. This review provides a deep insight into the recent research progress concerning the effects of MSC and macrophage-associated EVs on the pathogenesis of pulmonary fibrosis. In addition to discussing their respective vital roles, we summarize the importance of cross-talk, as macrophages are vital for MSCs to exert their protective effects through two major patterns, including attenuating macrophage activation and M1 phenotype macrophage polarization. Moreover, miRNAs are selectively enriched into EVs as essential components, and consideration is given to the particular effects of EV-associated miRNAs. [ABSTRACT FROM AUTHOR]

Mitochondrial dysfunction plays an essential role in secondary brain injury following traumatic brain injury (TBI). Interestingly, accumulating evidence has shown that therapeutic benefits of mitochondrial transplantation exist. Therefore, we hypothesized that the injection of exogenous mitochondria would contribute to the mitigation of cellular energy metabolism disorders and neurologic functions after TBI. We first extracted isolated mitochondria from fresh brain tissue using a kit and then identified their activity and purity. The role of exogenous mitochondria was assessed using the glucose oxygen deprivation–induced cellular damage model and controlled cortical impact–induced mice with TBI. The results showed that treatment with exogenous mitochondria improved the cellular respiratory control rate, the expression of tight junction-associated proteins, and synaptic plasticity-related proteins in vitro. Moreover, the application of exogenous mitochondria significantly reduced cellular apoptosis, promoted angiogenesis and alleviated brain edema and blood–brain barrier leakage in mice subjected to TBI. Additionally, exogenous mitochondria significantly reduced excessive inhibition of long-term depression in the hippocampus 7 days after TBI. Taken together, the data suggested that exogenous mitochondrial intervention ameliorated glucose oxygen deprivation–induced cell damage and controlled cortical impact–induced TBI in a mouse model. The new discovery in the current study inspires us to suggest that mitochondrial transplantation might serve as a new therapeutic strategy for TBI. [ABSTRACT FROM AUTHOR]

Purpose: Genetic factors play a vital role in intracranial aneurysm (IA) onset and development. Studying the relationship between IA and the Sox17 polymorphisms in diverse populations is essential for establishing credibility. Patients and methods: We collected blood samples derived from a total of 596 sporadic IA patients and 600 individual controls in several medical institutes in China. We used the Sequenom MassArray system for single nucleotide polymorphisms (SNPs) genotyping after DNA extraction. The SNPs data was tested and analyzed in PLINK (version 1.9). Multiple-testing was performed in PLINK to make the statistics more rigorous and accurate. Results: We found that the allelic G of rs1072737 (OR=1.303, genomic-control corrected P-value =0.001032) is a risk allele, while the allelic G of rs9298506 (OR=0.7253, genomic-control corrected P-value =0.01559) is a protective allele in Chinese Han people. Conclusion: The allelic G of rs1072737 is a risk factor for IA, while the allelic G of rs9298506 serves as a protective factor for IA in Chinese Han people. [ABSTRACT FROM AUTHOR]

Neuropsychiatric Disease and Treatment is an international, peer- Neuropsychiatric Disease and Treatment downloaded from https://www.dovepress.com/ by 202.164.43.126 on 09-Sep-2019 Copyright of Neuropsychiatric Disease & Treatment is the property of Dove Medical Press. [Extracted from the article]